Cases from The Ohio State University


Case 1: Dietary supplement-induced autoimmune-like hepatitis

The patient

A 41-year-old woman presented with 1 week of fatigue, diarrhea, post-prandial nausea, and vomiting followed by 2 days of painless jaundice. Her only significant medical history was endometriosis, and she did not have a history of alcohol or drug abuse. Physical examination demonstrated scleral icterus and jaundiced skin but no signs of chronic liver disease. Her abdomen was soft and nontender, and examination of the liver was unremarkable. Liver tests were notable for a total bilirubin level of 16 mg/dL (reference range, <1.5 mg/dL), alanine aminotransferase level of 1,369 U/L (reference range, 9 to 48 U/L), and aspartate aminotransferase level of 1,279 U/L (reference range, 14 to 40 U/L). Complete blood cell count was normal without eosinophilia. Acetaminophen level was undetectable, and viral hepatitis serologies were negative. Imaging with a right upper quadrant ultrasound and abdominal CT revealed no abnormalities. Subsequent laboratory evaluation found positive antinuclear (ANA) and anti-smooth muscle antibodies (SMA).

Liver biopsy showed a portal infiltrate of predominately neutrophils and lymphocytes mixed with plasma cells and scattered eosinophils. Further history revealed she had been taking a weight loss supplement (with label contents including green coffee bean extract, Garcinia cambogia fruit extract, and alpha lipoic acid) for approximately 3 months. Prednisone therapy was initiated, and she was instructed to abstain from all dietary supplements. Her liver function tests were improved at discharge and normal on 1-month follow-up.

The diagnosis

Our patient was diagnosed with drug-induced autoimmune-like hepatitis from her dietary supplement use. Supplements are defined as any product intended to add nutritional value to the diet, including herbs, vitamins, or minerals. A study from 2012 suggested that 1 out of every 5 U.S. adults report daily supplement use. Patients have been found to disclose their supplement or herbal use only 30% of the time to their treating clinicians, which makes it more difficult to diagnose supplement-related illness.

Supplements presently account for 20% to 70% of all drug-induced liver injuries. Patients may present with nonspecific symptoms such as anorexia, nausea, or diarrhea, but the most common presenting symptom is jaundice. Laboratory data for patients with drug-induced autoimmune-like hepatitis typically show a hepatocellular injury, although cholestasis may be evident as well. The diagnosis is made by clinical judgment but can be aided by autoantibody testing (specifically ANA and SMA) to help distinguish it from other drug-induced injuries. The histology is typically interface hepatitis and portal infiltrates of lymphocytes, plasma cells, and eosinophils, as seen in classic autoimmune hepatitis (AIH) and in this patient. While the mainstay of treatment is withdrawal of the offending agent, corticosteroids can be considered in severe disease or when the distinction between drug-induced and “classic” AIH is uncertain. When corticosteroids are used in treatment, the diagnosis of drug-induced AIH is supported by lack of relapse after withdrawal of the offending agent and corticosteroid treatment.

Pearls

  • The presentation of patients with drug-induced autoimmune-like hepatitis is clinically, serologically, and histologically similar to autoimmune hepatitis; the diagnosis is supported by a lack of relapse after treatment.
  • Dietary supplement use is an important potential cause of drug-induced autoimmune-like hepatitis.

Case 2: Splenic sarcoidosis

The patient

A 54-year-old woman presented with weakness, confusion, lightheadedness, and an unintentional 20-pound weight loss over the past 6 months. Her physical examination on admission was remarkable for lethargy. No lymphadenopathy or organomegaly was appreciated, and her lungs were clear to auscultation bilaterally. Initial laboratory testing was significant for a calcium level of 13.9 mg/dL, a creatinine level of 4.02 mg/dL (baseline, 1.0 to 1.5 mg/dL), white blood cell count of 6,300/µL, and hemoglobin level of 8.5 g/dL. Parathyroid hormone level was low, and thyroid function tests were normal. Serum protein electrophoresis was negative for a paraprotein.

CT of her chest, abdomen, and pelvis showed only enlarged paratracheal lymph nodes and an enlarged spleen. A bone scan was negative for lytic lesions. She was given aggressive intravenous hydration, vitamin D, furosemide, calcitonin, and bisphosphonates, but she remained hypercalcemic. A paratracheal lymph node biopsy showed benign lymphoid tissue and was negative for granuloma or malignancy. A bone marrow biopsy was similarly unrevealing. A positron emission tomography scan showed hypermetabolic activity throughout the spleen, concerning for malignant lymphoma, along with hypermetabolic lymph nodes in the abdomen and mediastinum. Despite medical therapy, serum calcium remained persistently elevated at greater than 10 mg/dL, and she remained symptomatic. Splenectomy was performed for diagnostic and therapeutic purposes, and histology revealed noncaseating granulomas. The patient's hypercalcemia durably resolved after splenectomy.

The diagnosis

The patient was diagnosed with refractory hypercalcemia secondary to splenic sarcoidosis. Only 10% of sarcoidosis is isolated in the spleen. Abdominal sarcoidosis is the most common extrapulmonary site of disease, and the liver and spleen are the most common locations therein. Splenic involvement is usually asymptomatic but can present with left upper-quadrant pain. Splenic sarcoidosis can cause hypersplenism, resulting in anemia, leukopenia, and thrombocytopenia. Clinical indications for splenectomy are hypersplenism, refractory hypercalcemia, functional asplenia, or enduring suspicion of malignancy. Primary management of extrapulmonary sarcoid consists of medical therapy with steroids, methotrexate, and/or antimalarial drugs. Patients with splenic sarcoid should have frequent follow-up to continue surveillance for the development of pulmonary and alternative extrapulmonary disease.

Pearls

  • The liver and spleen are the most common sites of extrapulmonary sarcoidosis.
  • Splenectomy is indicated in sarcoidosis in the event of progressive hypersplenism, refractory hypercalcemia, functional asplenia, or the enduring suspicion of malignancy.

Case 3: Hemophagocytic lymphohistiocytosis

The patient

A 23-year-old woman with a 1-year history of “lupus-like syndrome” presented with a 2-week history of fever, fatigue, weakness, and lower-extremity pain and swelling. Over the previous 6 months, she had a documented 50-pound weight loss and pancytopenia. Her family history was significant for Graves' disease and Raynaud's disease. Physical examination revealed a blood pressure of 88/51 mm Hg, heart rate of 93 beats/min, cold and clammy skin, slurred speech, and a slight hand tremor. No lymphadenopathy or splenomegaly was noted. Admission labs were as follows: white blood count, 5,400/µL; hemoglobin level, 8.8 mg/dL; platelets, 146,000 cells/µL; sodium level, 122 mEq/L; creatinine concentration, 1.2 mg/dL; and C-reactive protein level, 10.6 mg/L. Chest X-ray showed mediastinal lymphadenopathy.

Within a week of admission, her platelet count dropped to 42,000 cells/µL. Lactate dehydrogenase and bilirubin levels increased to 460 U/L and 11.0 mg/dL, respectively. Ferritin level was noted to be greater than 7,000 ng/mL (reference range, 10 to 291 ng/mL). ANA testing was negative. Abdominal CT scan revealed splenomegaly with large mediastinal and supraclavicular lymphadenopathy. Lymph node biopsy revealed extensive necrosis, along with evidence of mycobacterial organisms and Epstein-Barr virus (EBV). A bone marrow biopsy showed normal chromosomes with eosinophilia and hemophagocytosis. Interleukin-2 receptor was significantly elevated, and natural killer cell activity was reduced. Treatment was started with pulse-dose dexamethasone and weekly rituximab. Despite treatment, her respiratory and neurologic status continued to deteriorate, and her family made the decision to transition to palliative care.

The diagnosis

This patient was diagnosed with hemophagocytic lymphohistiocytosis (HLH) associated with mycobacterial and viral infection. HLH was first described as a clinical entity in 1939 and has published mortality rates as high as 95%. Primary HLH, which occurs in children, has been linked to specific genetic abnormalities. Secondary HLH occurs sporadically in adults and usually in association with a variety of infectious and autoimmune disorders. The pathophysiology is incompletely understood but involves the cytokine-mediated inflammatory pathway, with antigen-presenting cells stimulating CD8+ cytotoxic T lymphocytes. Infectious triggers include disseminated histoplasmosis, toxoplasmosis, mycobacterium (typical and atypical), cytomegalovirus, and EBV.

According to the Histiocyte Society, diagnosis of HLH requires at least 5 out of the following 8 criteria: fever; cytopenia (in 2 of 3 lines); splenomegaly; hypertriglyceridemia or hypofibrinogenemia; elevated ferritin level (>500 µg/L); hemophagocytosis in bone marrow, spleen, or lymph nodes; low or absent natural killer cell activity; and soluble interleukin-2 receptor level greater than or equal to 2,400 U/mL. This patient met 7 of the 8 criteria for HLH.

Treatment involves immunosuppression that targets activated macrophages and/or activated T-cells, and etoposide and systemic corticosteroids are currently recommended. Early use of etoposide has been associated with improved survival. Other treatment options may include methotrexate, interleukin-1 receptor antagonists such as anakinra, cyclosporine, or intravenous immunoglobulin.

Pearls

  • HLH is a rare disorder but should be considered in a patient with persistent fevers, cytopenias, and extremely high serum ferritin.
  • The mortality associated with HLH is extremely high, and treatment with immunosuppression should be initiated as soon as the diagnosis is made.

Case 4: Chronic progressive disseminated histoplasmosis

The patient

A 74-year-old man with a history of chronic obstructive pulmonary disease presented with fever for 8 weeks, anorexia, 30-pound weight loss, and night sweats. He resided in central Ohio and was formerly a heavy smoker. On physical examination, he was febrile and ill-appearing and had 92% oxygen saturation on 2 L of oxygen. He had no increased work of breathing. Lungs had diminished sounds with bibasilar rales. There was no palpable lymphadenopathy or hepatosplenomegaly. Other notable findings were thrush and what appeared to be a fungal balanitis.

Chest X-ray showed bilateral ground glass opacities. Chest CT demonstrated a left lower-lobe lung nodule, 1.6 × 1.2 cm, along with significant hilar, mediastinal, and supraclavicular lymphadenopathy and bilateral lower-lobe airspace disease. A bronchoscopy with endoscopic bronchial ultrasound was performed, which showed mucosal inflammation and mucoid secretions. Cytology from bronchoalveolar lavage and transbronchial biopsies did not show malignant cells. HIV testing was negative. Urine Histoplasma antigen was positive but below the limit of quantification. Histoplasma antibody by complement fixation (CF) was positive at 1:32 and immunodiffusion (ID) was positive for M band. The patient was placed on a loading then maintenance dose of itraconazole. Bronchoalveolar lavage and blood cultures later grew Histoplasma capsulatum.

The diagnosis

This patient's diagnosis was chronic progressive disseminated histoplasmosis, which is a characterization of the slowly progressive and generally fatal infection due to Histoplasma capsulatum in older individuals without overt immunosuppression. H. capsulatum is a fungus that is endemic to the Ohio and Mississippi River valleys, and disseminated disease occurs in approximately 1 in 2,000 patients with acute infection. Most patients who develop acute disseminated histoplasmosis are immunosuppressed, but it can also occur in immunocompetent older individuals. Chronic disseminated histoplasmosis is uncommon in older adults without immunosuppression; this patient has a rare case of the chronic progressive disseminated form without clear immunosuppression.

Chronic disseminated histoplasmosis usually develops over several months, and the disease is fatal if not treated. The symptoms include fever, malaise, anorexia, and weight loss. Physical examination often reveals hepatosplenomegaly, lymphadenopathy, pallor, and petechiae if pancytopenia is present; mucous membrane and skin ulcerations can be seen in approximately 5% of cases. Severe disease can present as severe sepsis, disseminated intravascular coagulation, renal failure, and acute respiratory distress.

The evaluation for disseminated histoplasmosis should include fungal blood cultures, tests for Histoplasma antigen in urine and serum, and Histoplasma immunodiffusion and complement fixation. Treatment is not needed for most patients who have acute pulmonary histoplasmosis, but chronic forms of the infection and severe disease such as chronic progressive disseminated histoplasmosis must be treated. First-line treatment depends on the severity of the disease and includes itraconazole or amphotericin B. Prompt recognition and treatment is important to prevent progression and possibly death.

Pearls

  • Chronic progressive disseminated histoplasmosis is a slow, progressive, and generally fatal infection by Histoplasma capsulatum that occurs in older adults without overt immunosuppression.
  • Treatment is usually not needed for most patients who have acute pulmonary histoplasmosis, but chronic forms of the infection and severe disease such as chronic progressive disseminated histoplasmosis must be treated with antifungals such as itraconazole or amphotericin B.