Cryptogenic cirrhosis
For patient information, click Cryptogenic Cirrhosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Imam Ali Shah, MBBS [2]
Synonyms and keywords: Idiopathic Cirrhosis
Overview
Cryptogenic cirrhosis (CC) is defined as cirrhosis of unknown origin. It is a diagnosis of exclusion and is only made after extensive investigative workup when the underlying cause of cirrhosis remains elusive. The cause of this condition is, by definition, unknown; however, there are correlations suggesting that metabolic dysfunction-associated steatohepatitis (MASH) plays a significant role . Advances in investigative methods, understanding of liver disease, and acknowledgment of metabolic dysfunction-associated steatohepatitis (MASH) as a plausible cause have led to a significant decrease in the use of this term.
Historical Perspective
Pathophysiology
Genetics
Genetic factors are increasingly being implicated in the occurrence of CC. Studies have found that thrombophilic and fibrogenic genetic factors and alterations in genes encoding hepatic lipid metabolism regulatory proteins are of particular importance in development and progression of CC.[1] [2] Genome-wide association studies have uncovered loss-of-function genetic variants that offer protection against liver diseases including CC. Of note is the loss-of-function mutation in one copy of the CIDEB gene, which was identified in a large exome sequencing study to be associated with a lower risk of cirrhosis from any cause.[3]
Associated Conditions
Cryptogenic cirrhosis has a strong association with metabolic disorders, including hypertension, dyslipidemia, diabetes, and hyperuricemia. However metabolic-dysfunction associated steatohepatitis must be ruled out to diagnose the condition.
Gross and Microscopic Pathology
CC has a similar histopathological findings to non-cryptogenic cirrhosis and is characterized by nodular liver morphology due to fibrous septa formation, dividing the liver into regenerative hepatocyte nodules microscopically. Fibrosis is prominent, disrupting the liver's architecture, with associated hepatocellular changes such as atrophy, hypertrophy, and fatty infiltration. Inflammation and necrosis may be evident, along with features like Mallory-Denk bodies, megamitochondria, and iron deposition, reflecting the chronic liver injury and regenerative processes ongoing within the liver.
Causes
Although the exact cause of cryptogenic cirrhosis remains uncertain, accumulating evidence and research increasingly suggest that metabolic dysfunction-associated steatotic liver disease (MASLD) may be the underlying factor.[4] Several studies have demonstrated the underlying role of genetic factors in occurrence and progression of CC.[5] [6]
Differentiating Cryptogenic Cirrhosis from other Diseases
While there's limited data explicitly differentiating the characteristics of cryptogenic cirrhosis from non-cryptogenic cirrhosis,studies have highlighted the following discernible differences between the two regarding the associations and complications of cirrhosis:
Metabolic Syndrome: Cryptogenic cirrhosis is significantly more prevalent in individuals with underlying metabolic derangements, including hypertension, dyslipidemia, diabetes, and coronary artery disease.
Cardiovascular disease: CC is associated with a higher incidence of cardiovascular disease.
Cancer: Studies have shown higher and earlier occurrence of hepatocellular carcinoma (HCC) and extrahepatic cancer in cryptogenic cirrhosis.[7] HCC also frequently presents at an advanced stage in patients with cryptogenic cirrhosis, likely due to insufficient surveillance measures. Consequently, treatment options are constrained, resulting in shorter survival periods.[8]
Epidemiology and Demographics
Age
Studies indicate that cryptogenic cirrhosis tends to occur more frequently in older individuals compared to non-cryptogenic cirrhosis, with some research suggesting an age difference of approximately ten years [9]. Additionally, it is more prevalent among individuals who have obesity, diabetes, and other metabolic comorbidities.
Gender
Cryptogenic cirrhosis is more common in females, which can partly be explained by higher prevalence of alcoholic liver disease in men globally.[10]
Race
No ethnic predilection has been observed in cryptogenic cirrhosis.
Developed vs. Developing Countries
Cryptogenic cirrhosis is a more frequent diagnosis in resource-limited and developing economies, probably due to lower availability of more advanced diagnostic modalities.
Risk Factors
Screening
Natural History, Complications and Prognosis
Cryptogenic cirrhosis is an irreversible chronic liver disease characterized by chronic liver injury, inflammation, fibrosis, and distortion and nodularity of liver architecture. The natural history of CC characterized by an asymptomatic phase, known as "compensated cirrhosis," followed by a progressive phase known as "decompensated cirrhosis". Decompensated cirrhosis is end-stage liver disease (ESLD) and is marked by the development of complications of portal hypertension and/or liver dysfunction, similar to non-cryptogenic cirrhosis.
Complications
Patients with cryptogenic cirrhosis are at risk of developing complications associated with advanced liver disease. These include portal hypertension and associated complications, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatocellular carcinoma, and death.
Prognosis
The prognosis of cryptogenic cirrhosis, like cirrhosis due to other etiologies, depends on various factors including the stage of cirrhosis at diagnosis, the presence of complications, and the response to treatment. An added factor influencing the prognosis of CC is the absence of an underlying cause, adding complexity and uncertainty to the selection and implementation of suitable therapies and interventions. Early diagnosis and intervention may improve outcomes, but cryptogenic cirrhosis still carries a significant risk of morbidity and mortality.
Diagnosis
Diagnostic Criteria
There are no standardized diagnostic criteria for CC and it is best defined by exclusion.
History
A directed history should be obtained to ascertain
Symptoms
"Type symptom here" is pathognomonic of the "type disease name here".
"Type non specific symptoms" may be present.
Past Medical History
Diagnosing CC requires a rigorous past medical history evaluations and the presence of any metabolic disorder needs to be ruled to diagnose the condition.
Family History
Physical Examination
Appearance of the Patient
Vital Signs
Skin
Head
Eyes
Ear
Nose
Mouth
Throat
Heart
Lungs
Abdomen
Extremities
Neurologic
Genitals
Other
Laboratory Findings
Electrolyte and Biomarker Studies
Electrocardiogram
Chest X Ray
CT
MRI
Echocardiography or Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Pharmacotherapy
Acute Pharmacotherapies
Chronic Pharmacotherapies
Surgery and Device Based Therapy
Indications for Surgery
Pre-Operative Assessment
Post-Operative Management
Transplantation
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
References
- ↑ Eslam M, Valenti L, Romeo S (2018). "Genetics and epigenetics of NAFLD and NASH: Clinical impact". J Hepatol. 68 (2): 268–279. doi:10.1016/j.jhep.2017.09.003. PMID 29122391.
- ↑ Mercado-Irizarry A, Torres EA (2016). "Cryptogenic cirrhosis: Current knowledge and future directions". Clin Liver Dis (Hoboken). 7 (4): 69–72. doi:10.1002/cld.539. PMC 6490261. PMID 31041033.
- ↑ Verweij N, Haas ME, Nielsen JB, Sosina OA, Kim M, Akbari P; et al. (2022). "Germline Mutations in CIDEB and Protection against Liver Disease". N Engl J Med. 387 (4): 332–344. doi:10.1056/NEJMoa2117872. PMID 35939579 Check
|pmid=value (help). - ↑ Verweij N, Haas ME, Nielsen JB, Sosina OA, Kim M, Akbari P; et al. (2022). "Germline Mutations in CIDEB and Protection against Liver Disease". N Engl J Med. 387 (4): 332–344. doi:10.1056/NEJMoa2117872. PMID 35939579 Check
|pmid=value (help). - ↑ Giannini EG, Marabotto E, Savarino V, Trevisani F, di Nolfo MA, Del Poggio P; et al. (2009). "Hepatocellular carcinoma in patients with cryptogenic cirrhosis". Clin Gastroenterol Hepatol. 7 (5): 580–5. doi:10.1016/j.cgh.2009.01.001. PMID 19418607.
- ↑ Perumpail RB, Liu A, Wong RJ, Ahmed A, Harrison SA (2015). "Pathogenesis of hepatocarcinogenesis in non-cirrhotic nonalcoholic fatty liver disease: Potential mechanistic pathways". World J Hepatol. 7 (22): 2384–8. doi:10.4254/wjh.v7.i22.2384. PMC 4598608. PMID 26464753.
- ↑ Rinaldi L, Nascimbeni F, Giordano M, Masetti C, Guerrera B, Amelia A; et al. (2017). "Clinical features and natural history of cryptogenic cirrhosis compared to hepatitis C virus-related cirrhosis". World J Gastroenterol. 23 (8): 1458–1468. doi:10.3748/wjg.v23.i8.1458. PMC 5330831. PMID 28293093.
- ↑ Giannini EG, Marabotto E, Savarino V, Trevisani F, di Nolfo MA, Del Poggio P; et al. (2009). "Hepatocellular carcinoma in patients with cryptogenic cirrhosis". Clin Gastroenterol Hepatol. 7 (5): 580–5. doi:10.1016/j.cgh.2009.01.001. PMID 19418607.
- ↑ Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ (1999). "Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease". Hepatology. 29 (3): 664–9. doi:10.1002/hep.510290347. PMID 10051466.
- ↑ Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ (1999). "Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease". Hepatology. 29 (3): 664–9. doi:10.1002/hep.510290347. PMID 10051466.