Introduction

Sarcoidosis is a multi-system disease with the ability to manifest within all organs of the body, involving the infiltration of non-necrotizing granulomas. that have unknown etiology - a small area of inflammation. The disease is frequently localized in the lungs and hilar lymph nodes (intrathoracic disease) in around 90% of clinically diagnosed patients.¹ 

However, extra thoracic involvement is common in 25-50% of patients, affecting the organ system in a mosaic way as 50-79% of patients show hepatic manifestation with systemic sarcoidosis although the majority of patients remain asymptomatic.² Moreover, sarcoidosis of the liver can have a broad clinical spectrum where some patients with hepatic granulomas go on to develop fulminant liver failure.³ 

Understanding the hepatic manifestation of liver sarcoidosis is essential as there are differences in susceptibility between different ethnic groups, For example, the prevalence of hepatic sarcoidosis within the African American community is at 140 per 100,000 compared to 50 per 100,000 for Caucasians.³ 

Sarcoidosis has such widespread clinical symptomatology that it requires a more thorough understanding of the multiorgan granuloma formation, but no clear diagnostic criteria have been established for hepatic sarcoidosis.³ 

Pathophysiology of Sarcoidosis

The noncaseating granulomas found in many organs with sarcoidosis result from an inflammatory cascade brought about by antigens of unknown origin. As sarcoidosis has several disease phenotypes and localizations, it is expected that there are numerous antigens triggering the immune response. 

Initially, these antigens are transferred to T lymphocytes (Th1) via the human leukocyte antigen (HLA) where they bind to the complementary Th1 receptors - triggering the release of many inflammatory cytokines like tumor necrosis factor (TNF-ɑ), interleukin-1 (IL-1), and IL-6.³ From this inflammatory cascade, more proinflammatory cytokines like interferon-Ɣ (IFN-Ɣ), IL-2, and IL-12 are released, recruiting monocytes and macrophages which convert to giant cells - forming sarcoidosis-associated granulomas.³ 

Since sarcoidosis has a heterogenous disease phenotype, it is proposed that several environmental causative agents induce disease phenotypes and their localization. Patients with disease restricted to the lungs may have only been exposed to particulates that cannot spread systemically due to a lack of permeability to the blood and lymphatic systems.⁴

On the other hand, patients with abnormal disease localization such as hepatic disease manifestation, the third-most common affected area, may be exposed to systemic infections with bacteria or viruses and contact with absorbable particles like dust or chemicals.^4,5,6 Interestingly, there seems to be a genetic element that increases one's risk of disease development since a person with a close relative suffering from sarcoidosis is five times as likely to develop the disease.⁶ 

An hereditary context for the disease can be seen by the presence of familial clustering, variations in disease susceptibility within differing ethnic groups, and increased concordance in monozygotic twins which suggests that genetic makeup may act in tandem with environmental causative agents. Genome-wide association studies have identified a major gene locus, 6p21, that increases susceptibility to sarcoidosis.⁷

The locus contains antigen-presenting elements like HLAs and regulatory genes such as Butyrophilin-like 2 proteins (BTNL-2) for T-cell activation. BTNL-2, a cofactor of CD80/CD86, has a suppressive effect on T-cell activation which may contribute to abnormal granuloma formation.⁷

Additionally, specific class HLA class II antigens have also been shown to increase polygenic risk to sarcoidosis with the ACCESS project highlighting that some HLA-specific alleles correspond to specific disease phenotypes and progression.⁷

Hepatic involvement in Sarcoidosis

As stated the liver is the third most common organ affected in sarcoidosis disease development with 50-79% of sarcoidosis patients showing hepatic granulomas manifestation with granulomas favoring the periportal and portal liver regions.^2,3 A total of 50% of sarcoidosis patients have extrathoracic disease development which includes skin lesions, uveitis, and splenic involvement.¹

Further adding to the phenotypic heterogeneity of sarcoidosis is the prevalence of cardiac, renal, nasosinusal, laryngeal, and neurological manifestations which impact less than 10% of sarcoidosis patients. Sarcoidosis can generally be considered a disease of early to middle age since 70% of clinical cases begin at the ages of 25 to 40.¹

Generally, the disease progression pathway takes on two forms such as: 

• A time-limited disease development where two-thirds of patients evolve through a self-remitting disease within 12-36 months¹
• A chronic disease course where 10-30% of patients develop systemic disease and require long-term medical treatment for diseases like portal hypertension and fulminant liver failure (seen in 0.012% of hepatic sarcoidosis patients)^1,3

Clinical presentation

Signs and symptoms of hepatic sarcoidosis are most commonly asymptomatic in 90% of cases with around 5-30% of patients showing nonspecific and clinically defined symptoms that can show in any part of the body or organ system.^6,8 These include: 

Nonspecific:

• Fatigue 
• Malaise 
• Anorexia 
• Weight loss 
• Pruritus 
• Fever 

Clinical:

• Jaundice 
• Hepatomegaly 
• Portal hypertension-related symptoms such as esophageal varices and ascites 

Upon presentation of nonspecific and clinical symptoms, diagnostic procedures to fully attain a sarcoidosis diagnosis are difficult due to the mosaic nature of disease manifestation. For the case of hepatic sarcoidosis, 24 to 31% of patients have mild liver function test derangements but angiotensin-converting enzyme (ACE) elevation seems to be the best biomarker for sarcoidosis but only when used in conjunction with pulmonary imagining to distinguish from antimitochondrial antibody-negative PBC - a biomarker for primary biliary cholangitis.^5,8 

Diagnostic evaluation

Liver function tests are normally used to assess if the liver may be impacted. These tests include measuring levels of bilirubin, alkaline phosphatase, and transaminases. Ultrasound may also be used to investigate the morphology of the liver, elucidating if any nodules or abnormalities in liver volume are present. MRI scans can then be used to search for lesions within the hepatic systems of the liver.

Imaging analysis for sarcoidosis is generally not sensitive enough to highlight the presence of hepatic lesions since only 5% are identified. These hepatic lesions may complicate imaging analysis since they can appear as ill-defined hypo-enhancing lesions that can be caused by several diseases such as benign cysts or malignant tumors. Imaging may only be effective in confirming extrahepatic lesions like portal hypertension or esophageal varices and further confirmed by upper endoscopy.⁸ 

Management and treatment

Initial treatment is guided by extrahepatic symptoms that are considered more serious as opposed to intrahepatic manifestations so steroids like corticosteroids are a common selection in the constricted arsenal against suspected hepatic sarcoidosis.³

In cases where hepatic sarcoidosis patients have a normal liver function and no evidence of cholestasis, then treatment is routinely observational, consisting of regular liver function tests like ACE tests and measuring of liver fibrosis via vibration-controlled transient elastography (VCTE) - a non-invasive method to stage liver fibrosis and used as an alternative to liver biopsy.⁸ 

For patients with cholestasis and symptoms relating to typical liver sarcoidosis then first-line treatment consists of corticosteroid treatment to reduce inflammation and the size of granulomas with a combination of immunosuppressants and biologic tumor necrosis factor antagonists.⁸ These immunosuppressants aim to reduce the inflammatory cascade that is activated during antigen presentations to Th1 cells via HLAs.

For patients that have progressed into fulminant liver failure and cirrhosis, liver transplantations are considered in conjunction with corticosteroid and immunosuppressant application to prevent graft rejections and inflammation. One important note is that the use of corticosteroids to reduce systemic inflammation most likely alleviates disease symptoms and does not have any impact on the progression of hepatic sarcoidosis to liver cirrhosis.³ 

As stated, most patients with asymptomatic sarcoidosis without cholestasis and extrahepatic manifestations do not require medical treatment and two-thirds of patients follow a time-limited disease pathway with 12-36 months.¹ The overarching goal of hepatic sarcoidosis is to prevent the progression to portal hypertension and cirrhosis - the leading causes of mortality amongst the hepatic sarcoidosis patient population.

However, a bottleneck in hepatic sarcoidosis treatment seems to be a lack of randomized control trials for therapy selections towards hepatic sarcoidosis so steroids are primarily used.³ The recovery profile for patients who have progressed into fulminant liver failure and who have received a liver transplant is optimistic, showing a 78 to 86.4% survival rate after one year and a 61% survival rate after 5 years post-transplantation.⁸ 

Prognosis and outcomes

The vast majority of hepatic sarcoidosis patients show an asymptomatic disease profile and two-thirds of sarcoidosis patients follow a self-remitting pathway whereby sarcoid granulomas can spontaneously subside and disappear without the need for treatment. For these patients without chronic sarcoidosis, simple lifestyle changes are required in combination with painkillers (Ibuprofen and paracetamol) to combat pain and flare-ups.⁹ The overall death rate of sarcoidosis is less than 5% and the amount of hepatic sarcoidosis patients developing fulminant liver failure is around 0.012%. 

Summary 

Hepatic sarcoidosis is a multisystem autoimmune disease that forms from non-necrotizing granulomas in various organs of the body, most commonly in the lungs and lymph nodes. Hepatic involvement occurs in around 50-79% of sarcoidosis patients, often asymptomatic but can progress into systemic chronic hepatic sarcoidosis that can cause life-threatening disease manifestations like portal hypertension and liver cirrhosis.

Both environmental and genetic factors play a role in disease development and progression with a higher prevalence amongst women and the African American community. Non-specific symptoms can include fever, fatigue, and weight loss but actionable symptoms can include jaundice and portal hypertension.

Most people do not require treatment and can expect recovery within 12 to 36 months, only receiving mild painkillers like ibuprofen and paracetamol. For patients with more severe sarcoidosis, steroids alongside immunosuppressants are prescribed to reduce inflammation. In the most severe cases of hepatic sarcoidosis such as portal hypertension and fulminant liver failure, liver transplantation and corticosteroids are considered. 

Hepatic sarcoidosis can be a complex disease to diagnose due to its multiorgan impact and crossover of symptomatology. It is essential to prevent patients with hepatic sarcoidosis from progressing into chronic disease and so if you are experiencing any ongoing symptoms highlighted here, consult a Healthcare Practitioner for further advice.