Continuing Education Activity

Cryptogenic cirrhosis is cirrhosis of uncertain etiology that lacks definitive clinical and histological criteria for a specific disease. Although the exact cause of cryptogenic cirrhosis is unknown, correlations suggest that non-alcoholic steatohepatitis (NASH) plays a dominant role. This activity outlines the evaluation and management of cryptogenic cirrhosis and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Identify the epidemiology of cryptogenic cirrhosis.
• Identify common exam findings in cryptogenic cirrhosis.
• Summarize the treatment and management options available for cryptogenic cirrhosis.
• Explain interprofessional team strategies for improving care coordination and communication to advance management of cryptogenic cirrhosis and improve outcomes.

Introduction

Cryptogenic cirrhosis is cirrhosis of uncertain etiology that lacks definitive clinical and histological criteria for a specific disease[1]. Cryptogenic cirrhosis accounts for nearly 5% to 30% of cases of cirrhosis and nearly 10% of liver transplants.[1][2][3] Although the exact cause of cryptogenic cirrhosis is unknown, there are correlations that non-alcoholic steatohepatitis (NASH) plays a dominant role.[1]

Etiology

Although the exact etiology of cryptogenic cirrhosis is unknown by definition, many causes have been implicated. These include NASH, occult ethanol intake, occult viral hepatitis, autoimmune hepatitis, occult biliary disease, hepatic vascular disease, celiac disease, mitochondriopathies, familial Mediterranean fever, systemic lupus erythematosus, Alstrom syndrome, abnormalities of apolipoprotein B with low low-density-lipoprotein cholesterol, short telomere syndromes, keratin 18 mutations, and glutathione S-transferase mutations.[1]

Epidemiology

Cryptogenic cirrhosis is attributed as the cause in nearly 5% to 30% of cirrhosis cases and about 10% of liver transplants.[1][2][3] Nearly half of the patients with cryptogenic cirrhosis are females, and the average age is about 60 years old.[1]

Pathophysiology

Although the exact cause of cryptogenic cirrhosis is unknown, there have been many potentially-associated diseases with cryptogenic cirrhosis that are described above. However, no definitive association has been made. Given the uncertain etiology, the pathophysiology of cryptogenic cirrhosis is unknown and thus requires further research into elucidating the underlying etiology before the pathophysiology can be determined.

Histopathology

Histological assessment is sometimes limited in those with advanced disease, but it can aid in determining the etiology of cryptogenic cirrhosis. A few studies have reported that in those being evaluated for late-stage cirrhosis and insufficient criteria to diagnose steatohepatitis, in the subgroup of patients who had a prior biopsy showing unequivocal nonalcoholic steatohepatitis had residual histological findings.[1][4] In these patients, the residual signs of steatohepatitis that remain include foci of macrosteatosis, cellular ballooning, and glycogenated nuclei.[1] Predominant type and distribution of inflammation, apoptotic bodies, bile ductular proliferation, and Mallory-Denk bodies may also be present on histology.[1]

History and Physical

Approximately 10% of cases of cryptogenic cirrhosis are discovered incidentally during evaluation of other issues such as possible gallbladder disease, and nearly 45% of patients only had complaints of vague symptoms such as fatigue or previously unexplained lab abnormalities.[1] However, nearly 45% of patients had complications of portal hypertension including new onset ascites, encephalopathy, or variceal bleeding[1]. Occasionally, patients with cryptogenic cirrhosis present with hepatocellular cancer.[1][5][6][7] Moreover, due to the close association between cryptogenic cirrhosis and nonalcoholic steatohepatitis, and as a result with metabolic syndrome, patients may present with both cardiovascular disease and cirrhosis.[1][8][9]

Important history to obtain would entail a prior diagnosis of fatty liver disease, obesity, diabetes, hyperlipidemia, exposure to blood or needles, family history of liver disease, personal or family history of autoimmune diseases, alcohol history, medication history such as methotrexate, and occupational history.[1]

Patients with cryptogenic cirrhosis may present similarly to those with cirrhosis from other known etiologies and may have signs and symptoms that include jaundice, altered mental status, palmar erythema, spider angiomata, abdominal distention, weight loss, edema, varices, asterixis, and other cause-specific findings.

Evaluation

Laboratory testing should include viral hepatitis studies, autoimmune profiles, quantitative immunoglobulin levels, iron studies, alpha-1-antitrypsin (A1A) phenotype and level, Wilson disease markers, and celiac disease markers.[1][10] Aminotransferase levels, such as AST and ALT, are typically only mildly elevated or normal in those with cryptogenic cirrhosis.

A definitive diagnosis will also require a biopsy. Histological markers include a predominant type and distribution of inflammation, cellular ballooning, Mallory-Denk bodies, glycogenated nuclei, foci of macrosteatosis, bile ductular proliferation, and apoptotic bodies.[1]

Treatment / Management

The definitive treatment for cryptogenic cirrhosis is transplantation. However, given the close association between cryptogenic cirrhosis and NASH, medical management until transplant may be beneficial. Lifestyle modifications such as weight loss, physical exercise, and a healthy diet are recommended. Although NASH is related to the development of cryptogenic cirrhosis, there are other potential associations as well. Specific treatment for those etiologies is also recommended.

Differential Diagnosis

Diseases that can be mistaken for cryptogenic cirrhosis are other etiologies of cirrhosis. The differential for the etiology of cirrhosis is broad and includes but is not limited to alcoholic liver disease, non-alcoholic fatty liver disease, hepatitis B and C, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, IgG4 cholangiopathy, recurrent bacterial cholangitis, bile duct stenosis, Budd-Chiari syndrome, right heart failure, Osler disease, hemochromatosis, Wilson disease, and alpha-1-antitrypsin deficiency.[11] A thorough history and physical exam with laboratory and imaging tests can detect diagnosis cirrhosis. Once cirrhosis is diagnosed, risk factors and further testing, including biopsy, can help determine the specific etiology of cirrhosis.

Medical Oncology

Those with a diagnosis of cryptogenic cirrhosis are at high risk of developing hepatocellular carcinoma. Given this risk, it is recommended that patients be screened every 6 months for hepatocellular carcinoma using ultrasound imaging of the liver. Other screening modalities exist such as computed tomography (CT) imaging, magnetic resonance imaging (MRI) and alpha-fetoprotein (AFP) lab testing. However, ultrasound imaging is the primary modality for screening. Often alpha-fetoprotein is an additional test along with an ultrasound but should not be used alone.

Prognosis

In the study by Rinaldi et al., they found that over a median follow-up period of 42 months, the percentage of deaths in those with cryptogenic cirrhosis was 39.2% compared to HCV related cirrhosis which was 30%.[12] Moreover, the median survival was 60 months for those with cryptogenic cirrhosis.[12]

The Model For End-Stage Liver Disease (MELD) score is a calculation aimed to determine the severity of end-stage liver disease and the need for transplantation. The components of the MELD score include creatinine, bilirubin, INR, and sodium.

Complications

Complications of cryptogenic cirrhosis include the same complications one would find with other causes of cirrhosis. These complications include hepatocellular carcinoma, hepatorenal syndrome, hepatopulmonary syndrome, variceal bleeding, ascites, spontaneous bacterial peritonitis (SBP), and hepatic encephalopathy. Additional potential complications for cryptogenic cirrhosis include heart disease, renal disease and other potential complications of diabetes such as retinopathy. Additional complications depend on the underlying etiology of cryptogenic cirrhosis.

Consultations

The care of a patient with cryptogenic cirrhosis includes a primary care physician along with a gastroenterologist, hepatologist, transplant team, nutritionist, and a social worker. A primary care physician has an important role in identifying those at risk of cirrhosis or liver disease and ordering the pertinent tests and imaging necessary for diagnosis before a consultant gets involved. A gastroenterologist can help progress the management of the patient's care and diagnose some of the complications associated with cryptogenic cirrhosis such as esophageal varices via endoscopy. A hepatologist can provide further expertise in additional treatment and management that will be beneficial. Once the patient is deemed a candidate for transplant, further planning including lab testing, imaging and history taking can be done by transplant hepatologists and surgeons. Given the close association between cryptogenic cirrhosis and NASH, nutritionists play a pivotal role in lifestyle and diet modification. Lastly, social workers are key members of the team as they can coordinate care between all the physicians and ensure the patient has travel accommodations not to miss appointments.

Deterrence and Patient Education

Cryptogenic cirrhosis can be a life-altering disease. For those patients at risk or who have a family history of liver disease, obesity, diabetes, hypertension, or hyperlipidemia are encouraged to see their primary care physician routinely. If one is at high-risk of cryptogenic cirrhosis, medication compliance, lifestyle and diet modifications, and surveillance are important. It is also imperative to follow up with a gastroenterologist and hepatologist for expert advice and potential placement for transplant.

Pearls and Other Issues

Although the exact cause of cryptogenic cirrhosis is unknown, nonalcoholic steatohepatitis is thought to have a large role. Metabolic problems such as diabetes, hyperlipidemia, and obesity have all been associated with the development of this disease. It is important that lifestyle and diet modification be encouraged in these patients. Also, once they develop cryptogenic cirrhosis, screening for hepatocellular carcinoma every 6 months is advised.

Enhancing Healthcare Team Outcomes

The management of cryptogenic cirrhosis, like all causes of cirrhosis, requires a team-based approach to have high-quality care. The coordination between primary care physicians, gastroenterologist, hepatologists, transplant hepatologists and surgeons, nutritionists, and social workers is vital to this care. An interprofessional, team-based approach to the care of a patient can help prevent many complications associated with cryptogenic cirrhosis and can potentially slow its progression if the specific etiology is targeted. For example, management of metabolic derangements in those with underlying NASH through lifestyle and diet modifications. Common complications of cryptogenic cirrhosis can include the need for a transjugular intrahepatic portosystemic shunt (TIPS), varices, ascites, SBP, hepatic encephalopathy. The management of these complications is much better when the care of the patient is coordinated between healthcare providers.[13] (Level I)