Atypical Presentation of Colonic Sarcoidosis and Current Diagnostic Challenges

STAGE 0 HEPATIC SARCOIDOSIS WITH SUPERIMPOSED PRIMARY BILIARY CIRRHOSIS

Cirrhosis Related to Hepatic Sarcoidosis in Older Adults

Hepatic Sarcoidosis (HS) should be considered in patients presenting with atypical fibrosis. A 37-year old African American man with type-2 diabetes presented with sudden onset left flank pain and nausea. His vitals were within normal limits except sinus tachycardia of 102/minute and examination was benign. Laboratory data including transaminases were normal. CT abdomen revealed left ureteral calculus (UC) and unexplained massive hepatomegaly. He underwent lithotripsy for the UC and was scheduled for a liver biopsy (LB). During the LB, he developed ventricular tachycardia with a rate of 254/minute, which required immediate electro-cardioversion followed by placement of Automated Implantable Cardioverter-Defibrillator (AICD). A transthoracic echocardiogram showed ejection fraction of 25-30%, with apical akinesis suggestive of Takotsubo cardiomyopathy (TC). Meanwhile, the LB showed minimal necrotizing granulomatous inflammation with atypical fibrosis on trichome stain, negative for amyloid, acid fast and fungal organisms as well as IgG4. Sarcoidosis was suspected, however, workup including angiotensin converting enzyme (ACE) levels, calcium, liver enzymes, bilirubin was normal, with the lack of pulmonary involvement on Chest x-ray. Endomyocardial biopsy confirmed non-caseating granulomas typical for sarcoidosis. In retrospect, we made a diagnosis of hepatic sarcoidosis (HS) along with TC. HS is seen in 50-80% of systemic sarcoidosis with only 10-30% presenting with abnormal liver enzymes. African American ethnicity and splenomegaly are risk factors. Clinically, HS can manifest with nonspecific fatigue, fever, or specific symptoms like jaundice, pruritus, abdominal pain while long standing disease can result in portal hypertension and end-stage liver disease. Cholestasis and liver involvement manifests as an elevation of ALP and /or GGT. Normal ACE levels don't rule out sarcoidosis but may distinguish it from other granulomatous diseases. CT may show hepatomegaly to multiple hypodense liver nodules. Definitive diagnosis requires histopathological examination of liver biopsy showing noncaseating granulomas, which are negative for fungal stains and acid-fast mycobacteria. Medical management is indicated if symptomatic or having cholestasis or in those at high risk of hepatic complications. IV steroids (10-20 mg/day) and ursodeoxycholic acid (20-40 mg/day) are the first line, while second and third line drugs include immunosuppressants.

Lungs are the most commonly affected organ in sarcoidosis, with extrapulmonary changes observed in 50% of cases. We detect liver damage in 11—80% of cases, with lower rates in clinically manifest cases and higher rates in incidental findings during liver biopsy. Despite all the achievements of world medicine, the exact cause of sarcoidosis remains unknown. Still, it is believed that the pathogenesis is multifactorial, including immunological and genetic mechanisms as well as the influence of environmental factors. Regarding the frequency of lesions in sarcoidosis, pathology of the lungs and lymph nodes predominates, with less often the liver. 90% of patients with systemic sarcoidosis have liver granulomas detected. Contrary to bilateral intrathoracic adenopathy, sarcoid changes in the lung parenchyma more frequently accompany hepatic sarcoidosis. While the presence of hepatic granulomas indicates a diagnosis of hepatic sarcoidosis, it is important to consider liver granulomas in the differential diagnosis as they can also occur in various systemic diseases. Granulomas in hepatic sarcoidosis are characterized by aggregates of epithelioid histiocytic and multinucleated giant cells, with lymphocytes and fibrin deposits predominantly at the periphery. These lesions are small, multiple, and evenly distributed throughout the liver parenchyma (although predominantly in the periportal and portal areas) and have the same maturation stage. Usually, there is no necrosis, but in some atypical cases, one may observe small areas of necrosis. Long­­standing lesions contain reticulin fibers within the granulomas, occasionally forming a prominent «cuff» of fibrosis. Large confluent granulomas may cause hyalinized scars. These changes, along with chronic intrahepatic cholestasis, may contribute to the development of micronodular biliary cirrhosis. Hepatic sarcoidosis may be presented with intrahepatic or extrahepatic cholestasis. Regarding histology, intrahepatic cholestasis in hepatic sarcoidosis looks like both primary biliary cholangitis and primary sclerosing cholangitis foci. Patients with hepatic sarcoidosis may develop non­­cirrhotic presinusoidal portal hypertension. Hepatic sarcoidosis is usually asymptomatic (50—80%), but when symptoms are present, the clinical spectrum may be broad. About 15% of cases exhibit pruritus and abdominal pain in chronic cholestasis. Jaundice is rare. 3—28% of patients experience cholestasis and fever, while fatigue is common. 5—10% of patients exhibit hepatomegaly and splenomegaly, particularly when portal hypertension is present. Predominantly elevated alkaline phosphatase levels (5—10 times the upper limit of normal) may be common. There is no specific serologic test to diagnose hepatic sarcoidosis. Since most patients with hepatic sarcoidosis are asymptomatic, they do not require specific drug therapy. However, in patients with symptoms of liver disease or patients with severe sarcoidosis and risk of liver complications or severe cholestasis, drug therapy should be considered. The most commonly used drug therapy options include corticosteroids and ursodeoxycholic acid. Second­­line therapy includes azathioprine, methotrexate, and infliximab. Liver transplantation should be considered in complicated cases with significant liver dysfunction.

Primary biliary cirrhosis (PBC) is an immune-mediated chronic progressive inflammatory liver disease leading to destruction of small interlobular bile ducts. Sarcoidosis is a chronic disorder of unknown etiology characterized by non-caseous granulomas. We reported a 69-year-old female patient with abdominal pain, malaise, vertigo, headaches, hands tremor and partial loss of hearing. Initial laboratory findings revealed elevated liver function tests and cholesterol with positive antimytochondrial and antinuclear antibodies. Liver biopsy revealed granuloma typical for PBC and granulomatous lesions typical for sarcoidosis. Elevated serum angiotensin-converting enzyme and granulomatous lesion on the brain magnetic resonance imaging (MRI) were detected and the patient was diagnosed with overlap of PBC and liver sarcoidosis and neurosarcoidosis. The patient was treated with ursodeoxicholic acid (UDCA) and prednisolone. Six months later the patient was symptom-free with laboratory findings within normal range. In PBC patients it is important to consider coexisting granulomatous liver diseases if elevated liver function tests persist despite UDCA therapy.

New sarcoidosis guidelines: Are we near to perfection?

Dear Editor:We read with great interest the case report1 on identifying olanzapine-induced liver injury in the setting of acute hepatitis C. We wanted to bring to the attention of the Mental Health Clinician readers our similar case report entitled "Olanzapine-induced elevated liver function tests in an older person with antidepressant-induced mania", who similarly experienced significant liver function test (LFT) elevation thought to be related to olanzapine that was published in The Senior Care Pharmacist in September 2022.2Although an increase in LFTs is a known adverse effect of antipsychotics including olanzapine, this is an underappreciated adverse effect, especially as the LFT elevation can be severe. Furthermore, there is no standard of care for monitoring LFTs at baseline or how frequently during antipsychotic treatment LFTs should be monitored.Brelje et al1 cites that olanzapine-induced liver injury has been shown to occur anywhere from 12 days to 8 years after initiating olanzapine, which is similar to what we found in published reports.1,2 In the case that Brelje et al reported, LFT elevation occurred after 6 days of olanzapine therapy and ALT peaked at 1510 IU/L.1 This is similar to the case recently published in The Senior Care Pharmacist of a 67-year-old male where LFT elevation began on day 6 of olanzapine treatment and peaked on day 8 with an AST of 2024 IU/L and ALT of 1508 IU/L.2If drug-induced liver injury or adverse effects of antipsychotics are topics of interest to the reader, we encourage you to read the Brelje et al1 article in the Mental Health Clinician as well as the Reid et al2 article in The Senior Care Pharmacist. The latter article reviews potential mechanisms of olanzapine-induced LFT elevation such as via a toxic intermediary metabolite or in relation to nonalcoholic fatty liver disease.2 Reid et al2 also summarizes 9 additional cases of olanzapine-induced LFT elevation.Brelje et al1 cites "large psychiatric professional societies have refrained from recommending widespread asymptomatic testing"(p213) of hepatic enzymes. However, both articles highlight how significantly elevated LFTs can become within 1 week of starting olanzapine treatment. We encourage readers to incorporate baseline monitoring and consider rechecking within 1 to 2 weeks of initiation with continued monitoring of LFTs in patients treated with antipsychotics including olanzapine into their routine practice.

Here we report a case of a 25-year-old woman with mesenteric and hepatic sarcoidosis without lung involvement complicated by severe noncirrhotic portal hypertension. In 1992, at the clinical presentation, she had abdominal pain, asthenia, and weight loss. Splenomegaly, signs of flogosis, sideropenic anemia, and cholestasis were observed. Laparoscopic abdominal exploration and histological analysis demonstrated noncaseating granulomas of the liver, abdominal lymph nodes, and mesenteric connective tissue. The clinical course was severe with episodic remissions and recrudescences characterized by ascites (mild or moderate), elevation of bilirubin levels (mean: 1.1 mg/dl; range: 0.9-3.5 mg/dl), reduction of albumin levels (mean: 4 g/dl; range: 3.4-4.2 g/dl), and prolongation of elevated international normalized ratio (mean: 1; range: 0.9-1.4). In 1997, the patient had variceal bleeding. Complete hemostasis was obtained with band ligation. Liver function was preserved, and until 2000 the disease remained stable. In 2001, the patient became pregnant. At the 36th week of gestation, the patient delivered a healthy female infant and afterwards remained in clinical remission. This report stresses that sarcoidosis can have a hepatic and mesenteric involvement in absence of thoracic lymphadenopathy. Portal hypertension may be severe, and in absence of cirrhosis it may be associated with portal thrombosis. Finally, portal hypertension in patients with hepatic sarcoidosis and preserved liver function should not be considered as an absolute contraindication to pregnancy.

A 49-year-old previously healthy male presented with 5 weeks of fatigue, malaise, nonproductive cough, and headache and elevated liver associated enzymes in a hepatocellular fashion. He reported no high risk sexual behavior and rare alcohol use; he denied illicit drug use, blood transfusions, tattoos, or recent travel. He endorsed occasional NSAID use prior to presentation, but denied other OTC or herbal medicines. He denied fevers, chills, weight loss, change in appetite, pruritus, abdominal pain, or change in bowel habits. On examination there was no stigmata of liver disease. His chronic viral hepatitis panel was negative as well as the rest of his work up; α-1 antitrypsin and ferritin; ANA negative, AMA negative, but anti-smooth muscle antibody weakly positive. A liver biopsy revealed diffuse non-caseated granulomata throughout all zones of the hepatic parenchyma without evidence of fibrosis consistent with granulomatous hepatitis. An ACE level was drawn due to concern for extrapulmonary sarcoidosis, which was elevated (93 U/L). Chest radiograph revealed a 2cm spiculated density in the right mid-lung but failed to demonstrate the hallmark hilar lymphadenopathy and reticular opacities of pulmonary sarcoidosis. Subsequent CT chest revealed a segmental opacity in the right middle lobe, and mediastinal lymphadenopathy. Hepatic sarcoidosis must be differentiated from other causes of granulomatous hepatitis including drug reaction, infection, and PBC. The negative AMA and normal serum IgM make PBC unlikely. Fungal and mycobacterial stains failed to demonstrate any fungal or mycobacterial organisms. Quantiferon, CMV serology, EBV PCR, Histoplasma serology, Lyme disease, and HIV testing were all negative. The elevated ACE level and CT findings support the diagnosis of hepatic sarcoidosis. Over the next few months with treatment, the patients' symptoms resolved and liver enzymes began to downtrend.Figure 1Sarcoidosis is a disease of unclear etiology, characterized by non-caseating granulomas in involved organs. Only 10% of patients with systemic sarcoidosis develop abnormal liver enzymes. Usually liver involvement is clinically silent and symptomatic patients usually present with a cholestatic pattern of liver injury. Our patient presented with several weeks of fatigue and found to have liver injury with a hepatocellular pattern which is a rare presentation of granulomatous hepatitis most likely representing hepatic sarcoidosis.

INTRODUCTION: Sarcoidosis primarily isolated to the liver—hepatic sarcoidosis (HS)—is rare and typically presents with non-specific gastrointestinal (GI) symptoms, abnormal liver enzyme levels, and radiological findings. We present a patient whom we determined to have HS. CASE DESCRIPTION/METHODS: A 33-year-old woman without significant past medical history presented with 3 months of worsening right upper quadrant pain and 35-40 lb weight loss. She had no other specific complaints. Her exam was notable for epigastric and RUQ tenderness. Her liver was palpable 4 cm below the costal margin. Lab results included Hgb 12.5 g/dL with MCV 79, AST 60, ALT 69, AP 629, and GGT 773. CT scan showed diffuse cyst-like lesions throughout the liver and spleen with peri-portal lymphadenopathy (Figure 1). The chest X-ray was unrevealing. Abdominal ultrasound showed hepatomegaly to 16.1 cm, splenomegaly to 13.1 cm, and periportal and peripancreatic lymphadenopathy. Her viral hepatitis workup, Chromogranin A, CEA, CA-19-9, CA-125, and AFP levels were unremarkable. Autoimmune hepatitis workup was negative. Her angiotensin converting enzyme (ACE) was elevated to 261 IU/L. EGD and colonoscopy were unremarkable, but we took random biopsies. Liver biopsy showed confluent, non-caseating epithelioid granulomas. Biliary destruction with lymphocytic cholangitis was noted (Figure 2). Our gastric biopsies showed non-necrotizing granulomas. We diagnosed her with HS without clinically or radiographically evident lung involvement. Since her symptoms later resolved, we opted against starting steroids and we referred her to the rheumatology and pulmonology services. DISCUSSION: Lung involvement is seen in 90% of sarcoidosis patients, usually in the upper lobes, hilar and mediastinal lymph nodes. The diagnostic criteria for sarcoidosis include clinical and radiographic signs, non-caseating granulomas, and exclusion of other diseases. Elevated ACE levels and non-caseating granulomas are not specific to sarcoidosis and can also be seen in primary biliary cholangitis. What clinched our diagnosis was the gastric biopsies that also showed granulomas. Those with asymptomatic liver disease can be monitored until liver enzymes normalize. Hepatomegaly does not necessitate medical treatment, although patients with weight loss and lymphadenopathy should have prednisone, generally for 12 months. Ursodeoxycholic acid (UDCA) can be given for pruritus and liver enzyme elevations. In advanced HS cases with cirrhosis, liver transplantation is the only recourse.

Hepatic sarcoidosis mimicking cholangiocellular carcinoma: A case report and literature review

End-stage liver disease as a consequence of hepatic sarcoidosis is a rare indication for liver transplantation. Consequently, there is a paucity of information on the pre-transplant findings and post-operative course of individuals transplanted for hepatic sarcoidosis. The purpose of this study was to evaluate our experience with liver transplantation for sarcoidosis. Cases were identified by review of the Mount Sinai Hospital liver transplant database. For each case, two control patients with other causes of liver failure matched for age, gender and date of transplant were selected for comparison. Hepatic sarcoidosis was the indication for liver transplantation in only seven of 2117 (0.3%) adult transplants performed from September 1988 to June 2004. The diagnosis of sarcoidosis was established by findings of extensive, non-caseating granulomas in pre-transplant liver biopsy specimens or in the native liver explant. Extrahepatic disease was limited to pulmonary involvement in four patients. Sarcoid cases were statistically more likely to have diabetes mellitus (100% vs. 21%, p = 0.001) and less likely to have antibodies to hepatitis C (0% vs. 50%, p = 0.047). Rates of acute cellular rejection were 57% in cases and 36% in controls (p = 0.397). Hepatic granulomas were identified in one patient at 5.6 yr of follow-up. Among cases, the 1-yr graft and patient survival rates were 100% and 5-yr graft and patient survival rates were 86%. The 1- and 5-yr graft and patient survival rates were comparable with those of patients transplanted for other indications.

Cardiac Sarcoidosis: There Is No Instant Replay

Hepatic sarcoidosis presenting as Budd Chiari syndrome leading to cirrhosis

Introduction: Sarcoidosis is characterized by non-caseating granulomatous inflammation in multiple organs. Over 90% of sarcoidosis manifests as intrathoracic lymphadenopathy and pulmonary involvement. Sarcoidosis is relatively rare in the gastrointestinal (GI) tract, especially in the colon. The most common site of sarcoidosis in GI tract is stomach. The clinical presentation includes diarrhea, constipation, and non-specific abdominal pain. We are reporting an uncommon presentation of colonic sarcoidosis in a patient with quiescent pulmonary sarcoidosis. Case Report: An 84-year-old African American woman presented with painless rectal bleeding. Her past history included sarcoidosis without steroid treatment, atrial fibrillation, gastroesophageal reflux disease, internal hemorrhoid, and adenomatous polyps resected 5 years ago. Physical examination was unremarkable. Initial laboratory findings revealed Hb 12.0 g/dL, platelet 123 K/μL, WBC 3.3 K/μL, Cr 0.7 mg/dL, and iPTH 59 (15-65 pg/mL). Elevated hypercalcemia, up to 12.9 mg/dL, was noted intermittently over the last 4 years; current calcium level 9.7 mg/dL. She underwent colonoscopy, which showed 2 adenomatous polyps and internal hemorrhoids. Hemorrhoidal bandings were performed. Normal colonic mucosa was found in the entire colon. Random colon biopsy revealed benign colonic mucosa containing epithelioid histiocytes (non-caseating granuloma) in the mucosa without focal necrosis. The CD 68 staining to differentiate Crohn’s disease from other chronic granulomatous diseases (CGD) was negative. The diagnosis of colonic sarcoidosis was made. No additional treatment was indicated since she was asymptomatic. Conclusion: Sarcoidosis rarely involves the GI tract. Establishing the diagnosis requires evidence of sarcoidosis in other organs and exclusion of other CGD, such as Crohn’s disease, mycobacterial infection, and fungal infection. The presentation of sarcoidosis in GI tract may be non-specific. Colonic sarcoidosis can occur as a colonic mass, polyposis, colitis, or even normal-appearing mucosa, which might be explained by the initial involvement of sarcoidosis in submucosal lymph tissue. Our case underscores that colonic sarcoidosis may be present in the absence of active pulmonary sarcoidosis. Treatment with glucocorticoids is only indicated for symptomatic cases.