Celiac Disease

Patients with celiac disease are usually younger than this one; however, an initial diagnosis after 60 years of age is not uncommon. Celiac disease is strongly associated with certain HLA types (HLA-DQ2 and HLA-DQ8) and is most common in persons of northern European descent. 

Classic gastrointestinal symptoms of celiac disease include those of malabsorption, such as steatorrhea, flatulence, and abdominal discomfort. Symptoms of celiac disease may range from fatigue and no gastrointestinal symptoms to profuse diarrhea with metabolic disturbances. Dermatologic manifestations include eczema and dermatitis herpetiformis, neither of which fits the description of this patient's skin lesions.

The sensitivity and specificity of IgA antibodies to tissue transglutaminase are greater than 94% in the absence of IgA deficiency; IgA deficiency can occur in up to 2% of persons with celiac disease. These negative results do not rule out a diagnosis of celiac disease, but they do reduce its likelihood. HLA testing could be considered if clinical suspicion for celiac disease is high despite negative serologic testing.

A biopsy specimen of the small bowel is a cornerstone of the diagnosis of celiac disease and typically reveals villous atrophy, crypt hyperplasia, increased intraepithelial lymphocytes, or a combination of these. There may also be an increase in intraepithelial lymphocytes in the colon. Although some features of this patient's small bowel–biopsy specimen resemble those of celiac disease, the findings are not specific for the diagnosis and may occur in cases of enteritis from other causes.

Adherence to a gluten-free diet should alleviate symptoms and signs of celiac disease.

Common Variable Immunodeficiency

A spruelike illness may occur in patients with common variable immunodeficiency (CVID). Patients with CVID have reductions in serum levels of IgG, IgA, IgM, or a combination of these. They also have poor responses to immunizations and often have recurrent infections, including sinopulmonary bacterial infections, opportunistic fungal infections, or protozoal infections. They may have seemingly paradoxical autoimmune manifestations, such as autoimmune cytopenias. Of patients with CVID, 20% have gastrointestinal manifestations (e.g., chronic giardiasis, spruelike illnesses, inflammatory bowel disease, protein-losing enteropathy, nonspecific malabsorption-like syndromes, or gastrointestinal lymphomas). Biopsy specimens of the small and large bowel may show pathological features that are indistinguishable from those of celiac disease. The diagnosis of CVID is usually made before the patient is 30 years of age.

Tropical Sprue

This patient was raised in a Caribbean country and had recently visited there. Tropical sprue, initially described by William Hillary in 1759, is endemic in many tropical regions, including the Caribbean. Characterized by chronic diarrhea, malabsorption, and nutritional deficiencies of folate and vitamin B12, tropical sprue should be suspected in anyone who has lived for more than a month in a region where the disease is endemic. Symptoms may develop up to several years after emigration. On examination of biopsy specimens, tropical sprue mimics celiac disease. The cause is presumed to be infectious, and treatment with broad-spectrum antibiotics is usually curative. Patients with tropical sprue usually present with voluminous diarrhea, which our patient does not have. Although I cannot rule out tropical sprue in this case, I believe there is a more specific diagnosis that will fit this case better.

Crohn's Disease

Crohn's disease must be considered in this patient. This disorder affects the small bowel in 80% of afflicted patents, and the terminal ileum is the most commonly involved site. However, symptoms can occur anywhere from the mouth to the anus. Histopathological examination of mucosal-biopsy specimens may reveal a spectrum of severity, from increased intraepithelial lymphocytes to frank ulceration and inflammation, with architectural distortion and noncaseating granulomas. 

Although the patient's symptoms are compatible with a diagnosis of Crohn's disease, epidemiologic factors make this diagnosis unlikely. In the United States, the prevalence of Crohn's disease in the Hispanic population is one tenth that in the white population. The incidence of inflammatory bowel disease is increasing in the developing world; however, in the United States, persons who have lived in latitudes closer to the equator before the age of 30 years have a lower risk of the development of inflammatory bowel disease than those who have lived in more northern latitudes. Finally, this patient's dermatologic manifestations do not resemble the extraintestinal manifestations of inflammatory bowel disease (i.e., pyoderma gangrenosum and erythema nodosum).

Strongyloidiasis

An important clue that emerges from the patient's clinical history is the incidental finding of S. stercoralis in the jejunum 4 years earlier. S. stercoralis is endemic in the tropics and subtropics; in the United States, it is often diagnosed in recent immigrants or U.S. military personnel who have recently returned to the United States. The life cycle starts in the soil, where rhabditiform larvae develop into infectious filariform larvae that penetrate the skin, enter the systemic circulation, penetrate the alveolar spaces, are coughed up and swallowed, and enter the gastrointestinal tract. In the small intestine, the organism matures and releases eggs that develop into rhabditiform larvae, which are typically excreted in the stool. Autoinfection may occur, usually in immunocompromised persons, in which rhabditiform larvae mature into filariform larvae in the gut and penetrate through the wall of the large intestine or the perianal skin into the systemic circulation.

Most cases of strongyloidiasis are asymptomatic or cause only mild symptoms. An acute manifestation is duodenitis, which causes abdominal pain, nausea, vomiting, diarrhea, or a combination of these. Ground itch is a severely pruritic cutaneous manifestation of the disease. Chronic autoinfection may result in enterocolitis and malabsorption, with diffuse involvement of the upper gastrointestinal tract and the proximal large bowel. Dermal migration of the larvae may result in urticaria, a feature consistent with this patient's skin lesions, and areas of serpiginous erythema, known as larva currens. Pulmonary manifestations include dry cough and asthmalike symptoms. Rarely, a syndrome similar to Löffler's syndrome can be seen.

In this case, the recurring abdominal symptoms, the rash, and the results of examination of gastrointestinal-biopsy specimens obtained during endoscopic evaluation are consistent with a diagnosis of enterocolitis caused by strongyloides. I think it is unlikely that the patient cleared the initial infection. In addition, his low-grade fevers, weight loss, and profound malnutrition raise concern for a syndrome known as hyperinfection.

Strongyloides Hyperinfection Syndrome

Hyperinfection with S. stercoralis is the accumulation of a large burden of parasites during the autoinfection cycle. Parasites accumulate primarily in the colon, more in the right colon than in the left colon. The parasitic burden in the colon may be so high as to trigger mucosal compromise and sepsis caused by gram-negative rods. Major risk factors for hyperinfection are infection with human T-cell lymphotropic virus type I (HTLV-I) or the human immunodeficiency virus (HIV), iatrogenic immunosuppression, malignant tumors, and hypogammaglobulinemia. Eosinophilia may be absent, as it is in this case. Mortality associated with strongyloides hyperinfection is estimated to exceed 10%.

Of all the risk factors, infection with HTLV-I is the most likely in this patient, in view of his history. HTLV-I is endemic in the Caribbean, South America, southern Japan, south and central Africa, and the Middle East. Transmission typically occurs vertically from mother to child through breast-feeding but can also occur from sexual contact, blood transfusions, or intravenous drug abuse. Infection with HTLV-I promotes a type 1 helper T-cell (Th1) response (characterized by interferon-γ production and the promotion of a cellular immune response to intracellular pathogens), rather than a type 2 helper T-cell (Th2) response (characterized by the production of interleukins 4, 5, and 13 and IgE, facilitating a humoral immune response to extracellular pathogens); therefore, the host defenses against extracellular parasitic infections such as strongyloides are effectively down-regulated. For this reason, HTLV-I infection is also associated with treatment failure. Stool examination for ova and parasites can be insensitive in patients without hyperinfection, but organisms are usually detectable in patients with hyperinfection. The presence of filariform larvae and rhabditiform larvae in the stool is a clue that autoinfection has occurred, and a high parasite burden suggests hyperinfection. Serologic tests for anti-strongyloides antibodies can be helpful, but endoscopic biopsies can greatly assist in making the diagnosis. In patients with disseminated disease and pulmonary symptoms, the organism may be found in the sputum.

In summary, I believe the likely diagnosis in this case is S. stercoralis hyperinfection, in association with HTLV-I infection. If stool examinations for ova and parasites are negative, I would recommend performing endoscopic examination of the upper and lower gastrointestinal tract and obtaining biopsy specimens to look for the organisms.

Dr. Eric S. Rosenberg (Pathology): Dr. Gala, you saw this patient on the consultation service. What was your thinking when you saw him?

Dr. Manish K. Gala: I saw this patient on the second hospital day as part of the gastroenterology consultation team. Our differential diagnosis was similar to Dr. Xavier's. For the reasons he summarized, we doubted the diagnosis of celiac disease and were concerned about recurrent strongyloidiasis with autoinfection and possible hyperinfection. We recommended HLA typing for the HLA-DQ2 and HLA-DQ8 phenotypes, the absence of which would rule out celiac disease; protein electrophoresis and testing for blood immunoglobulin levels to rule out CVID; and examination of stool specimens for enteric pathogens, ova and parasites, and fecal fat. We scheduled upper and lower gastrointestinal endoscopy for the next possible day (fifth hospital day).

DIFFERENTIAL DIAGNOSIS

Two weeks before admission, fever developed in this patient, with no other reported symptoms. It would be essential for the admitting physician to explore symptoms that might localize a source for the fever.  After this smoldering illness, she had a relatively sudden onset of acute abdominal pain, flank pain, and foul-smelling urine. The initial examination revealed fever, mild tachycardia, tenderness of the sternum and left costovertebral angle, and left-sided abdominal tenderness, particularly in the left lower quadrant.

DIFFERENTIAL DIAGNOSIS

Dr. Vijay Yajnik: This 80-year-old man with a complex medical history presented with a several-year history of intermittent abdominal pain, diarrhea, gastrointestinal bleeding, anorexia, and weight loss. Despite an extensive workup and multiple hospital admissions, a unifying diagnosis remained unknown. I will focus my differential diagnosis on several features of this case, including the findings on FDG-PET–CT (i.e., FDG uptake in several lung nodules, the stomach, and the ileocecal region), the identification of an ileocecal mass, an 8-mm induration at the site of a tuberculin skin test, and a positive interferon-γ release assay for Mycobacterium tuberculosis. Given this patient’s age and the constellation of findings, we need to consider processes that are likely to cause disease in the ileocecal region of the bowel, including cancer, Crohn’s disease, and infection.

Crohn’s Disease versus Intestinal Tuberculosis

Does this patient have Crohn’s disease or intestinal tuberculosis?  Misdiagnosis of Crohn’s disease in a patient with intestinal tuberculosis would result in treatment with glucocorticoids and biologic agents, which then has the potential to cause disease progression that leads to increased morbidity and mortality. Misdiagnosis of intestinal tuberculosis in a patient with Crohn’s disease would lead to prolonged antitubercular therapy and delay the necessary immunosuppression required to induce disease remission.

Both diseases have an insidious onset. Diarrhea, hematochezia, and extraintestinal manifestations are more common in patients with Crohn’s disease. Intestinal tuberculosis can target extrapulmonary sites in a manner that resembles the classic extraintestinal manifestations of Crohn’s disease, such as reactive arthritis, erythema nodosum, and uveitis. Ascites and fever are more commonly seen in patients with intestinal tuberculosis. Both diseases involve the ileum and colonic segments of the bowel. Isolated involvement of the terminal ileum is commonly seen in patients with Crohn’s disease, whereas involvement of the ileocecal area and a patulous ileocecal valve is seen in patients with intestinal tuberculosis. In patients with Crohn’s disease, mucosal injury has a cobblestone appearance with aphthous and longitudinal rake ulcers, whereas in patients with intestinal tuberculosis, the ulcers are transverse in orientation. Furthermore, the granulomas associated with intestinal tuberculosis are more frequent and confluent and larger than those associated with Crohn’s disease. Tissue samples are positive for acid-fast bacilli in only 25 to 30% of cases of intestinal tuberculosis. The use of molecular techniques, such as polymerase-chain-reaction (PCR) assays of fresh biopsy specimens, can improve the diagnostic yield.

On admission, this patient was ill but did not have diarrhea, hematochezia, extraintestinal manifestations, or a fistula, features that are commonly seen in patients with Crohn’s disease. An inflammatory mass was present on endoscopy, and examination of the biopsy specimen revealed granulomas without visible acid-fast bacilli. However, these findings do not rule out the diagnosis of intestinal tuberculosis, because detection of acid-fast bacilli has poor sensitivity, presumably due to low organism load. The patient is originally from Southeast Asia, where tuberculosis is endemic, and an interferon-γ release assay for M. tuberculosis was positive, thus indicating previous exposure. Tuberculosis can be dormant in patients for several decades, and reactivation can occur in patients with immunocompromise, long-term use of glucocorticoids, diabetes, renal failure, and cancer. This patient had several of these risk factors, including glucocorticoid use, renal failure, and diabetes. Taken together, these findings favor a diagnosis of intestinal tuberculosis. Given the high likelihood for tuberculosis, I would perform a repeat colonoscopy with a biopsy and send the tissue for histologic examination, culture, and PCR assay for tuberculosis.

Dr. Virginia Pierce (Pathology): Dr. Khalili, what was your impression when you initially evaluated this patient?

Dr. Hamed Khalili: We met this patient on the second hospital day to help with management of his bloody diarrhea and abdominal pain. He had previously received a diagnosis of Crohn’s ileocolonic disease; however, a number of atypical features — including his age, country of origin, and previous endoscopic findings — were not entirely consistent with Crohn’s disease. Nevertheless, noncaseating granulomas that had been noted in previous biopsy specimens were strongly suggestive of Crohn’s disease. Since he was an elderly man originally from Southeast Asia and had a previously positive interferon-γ release assay for M. tuberculosis, we considered the diagnosis of intestinal tuberculosis. Because of the similarities in clinical and endoscopic findings between intestinal tuberculosis and Crohn’s disease, it was particularly important to evaluate the patient more extensively for intestinal tuberculosis. Given his coexisting conditions, we also considered the possibility of ischemic colitis. However, we thought that diagnosis was unlikely because of the location of involvement in the bowel. 

Acute Midabdominal Pain (Acute Mesenteric Vein Thrombosis) Mayo Clic Proc 2014

Peptic ulcer disease is an important cause of epigastric pain and can lead to severe diffuse abdominal pain if perforation occurs. However, one would expect peritoneal signs in the acute phase due to chemical peritoneal irritation, followed by evidence of infection as a secondary bacterial peritonitis develops. Appendicitis is an important cause of midabdominal pain that can often start in the periumbilical area before localizing to the right lower quadrant. However, in the case of a ruptured appendix, one would also expect peritoneal signs. Acute cholecystitis is a common cause of abdominal pain. However, it typically occurs in the right upper quadrant with radiation toward the right shoulder. It is often associated with recent fatty food intake and nausea. Because our patient had the classic finding of pain out of proportion to the abdominal examination findings that is seen in various intestinal ischemic syndromes, acute MVT is the most likely cause of his symptoms. Abdominal aortic aneurysm is also an important cause of midabdominal pain, but the pain associated with abdominal aortic aneurysm often radiates to the back. Further- more, this patient lacks vascular risk factors or a smoking history, making this diagnosis less likely.

Computed tomographic angiography of the abdomen and pelvis with intravenous contrast is the ideal test for diagnosis of MVT because it can quickly visualize the bowel, surrounding structures, and vasculature. It is highly sensi- tive and specific up to 93% and 96%, respec- tively, in diagnosing mesenteric ischemia and can provide direct visualization of the thrombus. 

Abdominal radiography with an upright view that includes the diaphragm would be an ideal test to quickly identify a perforated viscus by revealing free intraperitoneal air. However, in this patient who lacks peritoneal signs, this test would not be helpful in identi- fying the cause of his pain. Furthermore, although acute MVT leading to intestinal ischemia may exhibit a characteristic thumb- print of mucosal edema or pneumatosis intes- tinalis, these findings are nonspecific, and further evaluation would be needed. (In essence, do not do Xray abdomen)

Doppler USG have its limitations as well, hence CTA is the best test to go for..

  

Unless it is in your DDx, you can never make a diagnosis...

Case 12-2014: (Acute Abdominal Pain) (Lead Poisoning)

DIFFERENTIAL DIAGNOSIS

Dr. Lawrence S. Friedman: This 59-year-old man presented with an acute illness characterized by epigastric pain, which was followed by more diffuse abdominal pain that worsened with eating. He also had an unusual constellation of symptoms that raises the possibility of a single underlying disease, and disorders that do not account for many of the features of this case can be easily ruled out.

Intraabdominal Causes of Acute Abdominal Pain

Acute abdominal pain has a broad differential diagnosis that includes both intraabdominal and extraabdominal causes. Life-threatening intraabdominal catastrophes, such as gastrointestinal perforation, intestinal infarction, and a ruptured abdominal aortic aneurysm, cause illness within minutes or hours and can be ruled out in this case by the length of the disease course and the lack of characteristic laboratory and imaging findings. Mesenteric ischemia without infarction can develop over a period of days, and abdominal pain that is disproportionate to the level of abdominal tenderness (as in this case) may be suggestive of mesenteric ischemia without infarction, particularly when the cause is mesenteric-vein or arterial thrombosis and when features of infarction (e.g., acidosis, an elevated lactate dehydrogenase level, and hyperamylasemia) are absent. In this case, a diagnosis of mesenteric ischemia is difficult to reconcile with the findings of a new anemia without clear evidence of gastrointestinal bleeding, the hyponatremia in the absence of intestinal infarction, and the absence of risk factors for mesenteric ischemia. A diagnosis of ischemic colitis in the absence of hematochezia would be unusual, and the findings are inconsistent with volvulus or an incarcerated hernia. Colonic obstruction, perhaps due to a neoplasm, has been ruled out by the CT findings; moreover, results of a colonoscopy had been normal 3 years earlier.

Common causes of acute abdominal pain — appendicitis, diverticulitis, cholecystitis, pancreatitis, and renal colic — as well as inflammatory bowel disease can be ruled out by the imaging and laboratory findings in this case. A bleeding peptic ulcer had been considered but was not confirmed on an upper endoscopic examination; also, the drop in hematocrit was not accompanied by gastrointestinal bleeding. Gastroenteritis was also suspected, but it was not consistent with this patient's clinical course.

The elevated blood levels of aminotransferases raise the possibility of hepatitis, but the severe pain and associated extraintestinal and laboratory features are not typical of the common hepatitis viruses or of a drug-induced hepatitis. Other infections that may involve the liver and have protean extrahepatic manifestations, such as visceral larva migrans, are unlikely because of the absence of eosinophilia, pneumonitis, and other characteristic features. This patient could have the complications of long-term alcohol use and the laboratory abnormalities associated with alcoholic hepatitis, but in that case, the blood level of aspartate aminotransferase would be higher than the blood level of alanine aminotransferase; also, in light of the severity of symptoms, evidence of hepatic dysfunction would be expected. The age of the patient makes Wilson's disease and other metabolic disorders, such as hereditary tyrosinemia, unlikely. Furthermore, the symptoms are inconsistent with nonalcoholic fatty liver disease and the Budd–Chiari syndrome. The elevated aminotransferase levels may be a nonspecific component of a systemic process.

Extraabdominal Causes of Acute Abdominal Pain

The constellation of features suggests that an extraabdominal cause of acute abdominal pain is most likely. Most entities in this category can be easily ruled out, because the diagnosis must explain the colonic pseudo-obstruction, the acute anemia without apparent gastrointestinal bleeding, and the acute hyponatremia, which appears to be caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Acute porphyria should be considered in a patient with acute, generally recurrent, severe abdominal pain that does not have a clear explanation. Features of this case that are consistent with a diagnosis of acute porphyria include severe neuropathic abdominal pain, nausea, stress or restlessness, pain in the arms and legs, constipation, colonic pseudo-obstruction, tachycardia, episodic hypertension, and SIADH; however, the characteristic dark urine was not present. Porphyrias are generally inherited and are caused by a deficiency in the activity of one of the enzymes required for normal heme synthesis. 

Microcytic Anemia NEJM 2014

They are categorized according to clinical presentation (neurovisceral or cutaneous) and according to the principal source of overproduction of porphyrins and porphyrin precursors (typically, the bone marrow or the liver). Patients with an acute neurovisceral porphyria, most commonly acute intermittent porphyria, may present with colicky abdominal pain, often in the lower abdomen. Patients with hereditary coproporphyria and those with variegate porphyria may present with either neurovisceral features or cutaneous features. Porphyria can be triggered by starvation, a negative energy balance, the use of drugs or alcohol, smoking, infections, and other forms of stress. This patient is 59 years of age, and a first attack of porphyria at this age would be unusual. Alcohol could have precipitated an attack, but pirbuterol is not included on the American Porphyria Foundation list of drugs that provoke attacks of acute porphyria or on other similar lists.

Causes of Dysgeusia and Basophilic Stippling

This patient could have had acute porphyria, but two findings that must be explained by the diagnosis are dysgeusia and basophilic stippling, and these are not known features of porphyria. Common causes of dysgeusia are chemotherapeutic agents, such as cyclophosphamide and cisplatin, and other drugs, such as albuterol, histamine H1-receptor antagonists, penicillamine, metronidazole, and boceprevir; it is also associated with conditions caused by exposure to pesticides and other toxins, such as lead poisoning, as well as zinc deficiency and xerostomia. Dysgeusia is a known side effect of pirbuterol.

Basophilic stippling is a hallmark of sideroblastic anemia and of lead poisoning, although it is not a constant feature of the latter. It is also seen in patients with arsenic poisoning, some thalassemias, a deficiency of erythrocyte pyrimidine 5'-nucleotidase, or thrombotic thrombocytopenic purpura.

Dysgeusia and basophilic stippling were distinct and prominent features in this case, although it is possible that nausea may have been perceived as altered taste. Arsenic poisoning causes a garlicky odor in the breath instead of true dysgeusia, and it is characteristically associated with severe diarrhea and cardiovascular symptoms, findings that were not seen in this case.

Lead Poisoning

I believe the most likely diagnosis in this case is lead poisoning, which explains all the clinical, laboratory, and imaging features, including the abdominal pain (“lead colic”), nausea, dysgeusia, constipation, colonic pseudo-obstruction, joint and muscle pain, behavioral and cognitive changes, acute anemia, basophilic stippling, SIADH, and decline in the blood level of phosphorus (which may be due to renal phosphate wasting). Lead lines, or bluish pigmentation at the gum–tooth line caused by a reaction of lead with dental plaque, are not a reliable indicator of acute lead poisoning and were absent in this patient. Deposition of lead in bones may be seen with long-term exposure, as may hypertension and neuropsychiatric effects. The diagnosis of lead poisoning is confirmed by measuring the blood lead level; a level of 10 μg per deciliter or higher is considered elevated in adults. The level may be higher than 100 μg per deciliter in patients with acute lead poisoning, which is much less common than chronic lead poisoning. Heme synthesis is impaired when 5-aminolevulinic acid (ALA) dehydratase is 80 to 90% inhibited; this occurs at a blood lead level of approximately 55 μg per deciliter.  Because of the inhibition of ALA dehydratase and the overproduction of ALA, patients with lead poisoning or with hereditary tyrosinemia type 1 classically present with features that are similar to those of patients with acute porphyria. Indeed, plumboporphyria, a porphyria that is caused by a deficiency of ALA dehydrates, is named for “plumbum” (Latin for “lead”) because symptoms of the condition mimic those of lead poisoning, but plumboporphyria is rare and is generally reported in children. An elevated urine or blood level of ALA is often helpful in establishing a diagnosis of lead poisoning, although patients with lead poisoning and patients having an attack of acute porphyria would both be expected to have this laboratory abnormality. However, only patients with acute porphyria would also have an elevated porphobilinogen level. Free erythrocyte protoporphyrin and zinc protoporphyrin levels, which show the effect of lead on hemoglobin synthesis, can also be used as indicators of lead exposure over the preceding 3-month period.

Mesenteric Circulation

The mesenteric circulation is extremely complex. Three primary vessels — the celiac artery, superior mesenteric artery, and inferior mesenteric artery — interconnect through collateral networks between the visceral and nonvisceral circulations. These interconnections ensure that the loss of a single vessel does not lead to catastrophic malperfusion of the viscera.

The acute occlusion of a single vessel (typically the superior mesenteric artery) in acute mesenteric ischemia can result in profound ischemia caused by the loss of blood flow through this key vessel and its collateral vascular network. In contrast, in patients with chronic mesenteric ischemia, additional collateral networks develop over time; symptoms often do not appear until occlusion of two or more primary vessels occurs.

Causes of Altered Circulation and Mechanism of Injury

The causes of altered mesenteric circulation are themselves often the result of obstruction or diminished blood flow, with a resulting decrease in oxygen delivery to a level that is insufficient to meet the metabolic needs of the visceral organs. Vasodilatation is the initial response, but prolonged ischemia leads to vasoconstriction, which can persist even after intestinal blood flow returns to normal.This early injury primarily affects the intestinal mucosa and submucosa and potentially impairs mechanisms that prevent the translocation of bacteria from the intestinal lumen.

This sequence of events can result in the activation of systemic inflammatory pathways and ultimately in worsened vasospasm, further regional ischemia, and more extensive injury to the bowel wall. Without intervention, the damage can progress to full-thickness injury, infarction, and death.

History and Physical Examination

Early attention to the details of the patient’s history and to findings on examination that indicate the presence of mesenteric ischemia is critical for timely diagnosis and treatment. In contrast to other vascular disorders, mesenteric ischemia primarily affects women; more than 70% of persons with this disorder are female.

The physician should assess the patient’s records and the results of the examination for any evidence of other atherosclerotic and vascular diseases, including peripheral artery, cerebrovascular, coronary artery, and renovascular disease. In addition, other pulmonary and cardiovascular conditions must be identified and managed, since they are often coexisting conditions in patients with mesenteric disease and they may limit the available options for revascularization.

Manifestations of Acute Mesenteric Ischemia

Patients with acute mesenteric ischemia may initially present with classic “pain out of proportion to examination,” with an epigastric bruit; many, however, do not. Other patients may have tenderness with palpation on examination owing to peritoneal irritation caused by full-thickness bowel injury. This finding may lead the physician to consider diagnoses other than acute mesenteric ischemia. In a patient with abdominal pain of acute onset, it is critical to assess the possibility of atherosclerotic disease and potential sources of an embolus, including a history of atrial fibrillation and recent myocardial infarction. During the examination, the patient’s description of the history and symptoms can be unclear because of changes in mental status, particularly if he or she is elderly.

Differentiation between arterial and venous obstruction is not always simple; however, patients with mesenteric venous thrombosis, as compared with those with acute arterial occlusion, tend to present with a less abrupt onset of abdominal pain. Risk factors for venous thrombosis that should be evaluated include a history of deep venous thrombosis, cancer, chronic liver disease or portal-vein thrombosis, recent abdominal surgery, inflammatory disease, and thrombophilia.

Manifestations of Chronic Mesenteric Ischemia

Patients with chronic mesenteric ischemia can present with a variety of symptoms, including abdominal pain, postprandial pain, nausea or vomiting (or both), early satiety, diarrhea or constipation (or both), and weight loss. A detailed inquiry into the abdominal pain and its relationship to eating can be enlightening. Abdominal pain 30 to 60 minutes after eating is common and is often self-treated with food restriction, resulting in weight loss and, in extreme situations, fear of eating, or “food fear.” 

An extensive gastroenterologic workup, possibly including cholecystectomy and upper and lower endoscopy — tests that are often negative in patients with chronic mesenteric ischemia — is generally carried out before the diagnosis is made. An important distinction is that many of these alternative processes do not involve weight loss, whereas it is common in cases of mesenteric ischemia. Since older age and a history of smoking are common in these patients, cancer is often considered, and concern about it may delay the identification of chronic mesenteric ischemia. Nonetheless, particularly in the case of elderly women with a history of weight loss, dietary changes, and systemic vascular disease, chronic mesenteric ischemia must be seriously considered and evaluated appropriately.

Laboratory Studies

• assessment of fluid, electrolyte, and acid–base status and evaluation for infection. 
• Many patients present with acidosis due to dehydration and decreased oral intake. However, lactic acidosis often indicates at least segmental, severe ischemia or irreversible bowel injury. It is not helpful to wait for evidence of increasing serum lactate levels to proceed with further testing; ideally, in fact, intervention would occur in patients with acute mesenteric ischemia before lactic acidosis develops, with the goal of saving additional intestine from full-thickness injury. A left shift in the ratio of immature to mature neutrophils or an elevated white-cell count may indicate full-thickness injury to the bowel wall or ischemia with bacterial translocation.
• Serum biomarkers have not proved to be as valuable for the early detection of acute mesenteric ischemia as was initially hoped. Despite the many investigations conducted to date, no clinically useful biomarkers have been identified, probably owing to the hepatic metabolism of complex proteins secreted by the intestine. Tests for markers of nutritional status, such as albumin, transthyretin, transferrin, and C-reactive protein, are the only studies of value in cases of chronic mesenteric ischemia, since they can be used to assess the degree of malnutrition before revascularization is undertaken.

Psoriasis

We need to ask a few questions about this patient's history of psoriasis. What was the extent of involvement? Had there been joint involvement? How had the illness progressed over the years? Which treatments had he received? Had he received biologic agents? How did the psoriasis affect his life? We should ask these questions to estimate the potential for illnesses associated with psoriasis or long-term consequences. Associated illnesses include psoriatic arthritis, cardiovascular disease, depression, anxiety, nonmelanoma skin cancer, and lymphoma. I am particularly concerned about lymphoma in this patient with widespread lymphadenopathy and abnormal findings in the spleen, because a number of studies suggest that patients with psoriasis have an increased risk of lymphoma. Because of the potential association between psoriasis and lymphoma, we need to include lymphoma in our differential diagnosis.

Erythema Nodosum

Next, we should investigate the patient's history of erythema nodosum. At the time of the episode, was another diagnosis made? How long did the episode last? Were there other symptoms? Did he receive any treatment? Was a chest radiograph obtained? In fact, when I reviewed the radiology report for this case with Dr. Muse, it became apparent that a radiograph had been obtained as part of the evaluation for erythema nodosum and showed a right hilar fullness and a right paratracheal density, features possibly consistent with lymphadenopathy. The potential presence of lymphadenopathy at least 3 years earlier was reassuring and led me to feel more certain about the diagnosis in this case.

Erythema nodosum has been associated with bacterial infections, viral infections, mycoses, drug use (e.g., antibiotics and oral contraceptives), malignant diseases (e.g., lymphoma, leukemia, and other cancers), and other systemic diseases (e.g., sarcoidosis, enteropathies, Sweet's syndrome, and Takayasu's disease). Many diseases are associated with erythema nodosum, and among patients in whom a cause of erythema nodosum is identified, streptococcal infection and sarcoidosis are fairly common diagnoses. However, in most patients, an underlying diagnosis is not made. On the basis of this patient's history, streptococcal infection seems unlikely. However, the presence of lymphadenopathy and the history of erythema nodosum may point toward a diagnosis of sarcoidosis.

Sarcoidosis and Löfgren's Syndrome

When erythema nodosum developed in this patient, he also had ankle pain and, within a month, an episode of arthritis of the right knee that prompted joint aspiration. The combination of erythema nodosum and ankle pain should raise the possibility of a diagnosis of Löfgren's syndrome, although the presence of hilar lymphadenopathy is generally also required for this diagnosis. Löfgren's syndrome is a form of sarcoidosis that is characterized by the triad of erythema nodosum, arthralgias, and hilar lymphadenopathy; it is usually self-limited, although its manifestations may persist for several years. A small number of patients with Löfgren's syndrome have normal chest radiographs at the time of diagnosis; most patients have hilar lymphadenopathy, 13% of patients have respiratory symptoms, and 4% of patients have peripheral lymphadenopathy. Furthermore, 6% of patients have a recurrence of sarcoidosis within 18 months to 20 years after presenting with Löfgren's syndrome. I think the episode of erythema nodosum, the ankle pain, and the knee arthritis were manifestations of Löfgren's syndrome, in which case, sarcoidosis would be the leading potential diagnosis.

Does sarcoidosis account for the other features of this patient's presentation ? Gastrointestinal manifestations of sarcoidosis primarily involve the stomach, and patients can present with abdominal pain, nausea, vomiting, and weight loss. Headaches, such as the one this patient reportedly had during the weeks before admission, are sometimes a manifestation of sarcoidosis. The patient's hypoattenuating splenic lesions are consistent with sarcoidosis. 

Are the findings on this patient's chest imaging consistent with sarcoidosis? Approximately 85% of patients with sarcoidosis have intrathoracic lymphadenopathy, typically bilateral hilar and right paratracheal lymphadenopathy. When I reviewed the radiograph before this conference, I was impressed by the predominance of the findings in the upper lung and the coexistent mediastinal lymphadenopathy, features that suggest sarcoidosis. Given the findings on the chest radiograph in this case, I strongly suspect that the diagnosis is sarcoidosis, although there are still a few issues to address.

We still need to consider the minimally elevated blood level of ACE. When the ACE level is less than 25 U per liter, the likelihood ratio for sarcoidosis is 0.12; when the ACE level is between 25 and 71 U per liter, the likelihood ratio is 1.31; and when the ACE level is greater than 71 U per liter, the likelihood ratio increases to 7.15. This patient had an ACE level of 55 U per liter, and therefore the probability of sarcoidosis was slightly increased, although the clinical and radiographic findings already made sarcoidosis an overwhelmingly likely diagnosis.

The next issue is to rule out the potential diagnoses of lymphoma and infection. The three possible areas to target for a tissue biopsy are the inguinal region, the chest (which could be evaluated with a transbronchial biopsy), and the spleen (which could potentially be removed). The safest area in which to perform a biopsy should be selected. The inguinal nodes would be the safest to access, although a transbronchial biopsy would also be a reasonable approach for obtaining a tissue sample in this case.

Dr. Eric S. Rosenberg (Pathology): Dr. Strom, what was your impression when you initially evaluated this patient?

Dr. Strom: We thought that this patient's abdominal pain was probably due to indigestion and was unrelated to the subacute disease process. Our differential diagnosis for the subacute disease process was sarcoidosis, tuberculosis, endemic fungal infection, granulomatous polyangiitis, and lymphoma. Given the presence of several enlarged lymph nodes and the development of night sweats, we were most concerned about lymphoma.