Tag Archives: Hereditary Angioedema

Liver Briefs: Hereditary Angioedema/Liver Transplantation, Bulevirtide/PEG for HDV, and AASLD Cystic Fibrosis Guidance

Posted on by

NE Peters et al. NEJM 2024; 391; 56-59. Normalization of C1 Inhibitor in a Patient with Hereditary Angioedema

“An infant with genetically confirmed hereditary angioedema and low C1 inhibitor levels (but without previous episodes of angioedema) underwent liver transplantation for biliary atresia, an unrelated condition. Liver transplantation led to normalization of the C1 inhibitor level and function. To our knowledge, this represents the first patient to be potentially cured of hereditary angioedema.” This case report shows that liver-directed therapy can reverse hereditary angioedema.

Related blog posts:

T Asselah et al. NEJM 2024; 391:133-143. Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D

Key finding: At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. 

My take: This is a long (48 weeks) and difficult treatment (2 injection meds and lots of peginterferon side effects). However, there is a fairly good response rate.

Related blog post: Image Only: World Hepatitis Day Infographic

ZM Sellers et al. Hepatology 2024; 79(5):p 1220-1238, May 2024. Open Access! Cystic fibrosis screening, evaluation, and management of hepatobiliary disease consensus recommendations

This link to the article also has links to related AASLD guidelines (eg. management of portal hypertension). Table 2 summarizes the ~34 recommendations which include yearly evaluation with labs, ultrasound at least every 2 years in pediatric patients (age 3 yrs and older) and against routine use of ursodeoxycholic acid.

A “Swell Diagnosis” (part 2)

Posted on by

Recently, this blog post reviewed a case presentation of hereditary angioedema which often presents with bouts of severe abdominal pain: “A Swell Diagnosis”

Now, a study has shown how this can be effectively treated with CRISPR gene editing:

  • HJ Longhurst et al. N Engl J Med 2024; 390:432-441. CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema.

My take: Gene therapies have been very expensive. If this therapy is approved for hereditary angioedema it will be too. However, some of the current treatments for preventing hereditary angioedema are also quite costly.

Related blog posts:

“A Swell Diagnosis”

Posted on by

J Allam et al. NEJM 2024; 390-71-76.A Swell Diagnosis

This clinical problem-solving case report describes a previously healthy 19 yo male with sudden-onset severe diffuse abdominal pain. His ED evaluation was unremarkable (including labs [CBC/d, CMP, Lipase, CMP, thryotropin, ESR, CRP and UA], and EKG). He was discharged after 3 hours. Over the next 10 years, he presented to the ED on numerous occasions with the same symptom complex and normal labs/mostly CT scans. One CT scan showed small-bowel thickening thought to be due to AGE. Ultimately, his symptoms increased to every 2 weeks. Extensive evaluations (multiple panendoscopies, MRCP, MRE, U/S, and infectious workup) were undertaken and numerous treatments were given without benefit. Ultimately, a CT scan showed remarkable circumferential wall thickening in the jejunum (see below). This led to evaluation for hereditary angioedema.

The article serves as a good review of this disorder and of the differential diagnosis.

Key points:

  • Background: Hereditary angioedema, which is due to a deficiency of functional C1 inhibitor protein, is a rare autosomal dominant genetic disorder that affects approximately 1 in 50,000 persons worldwide.1 
  • Mean age of onset : 8 to 12 years, and symptoms often worsen during puberty.1
  • Presentation: The disease is characterized by recurrent episodes of swelling in various parts of the body and can be severely debilitating. The hallmark symptom of hereditary angioedema is localized swelling of the skin and submucosal tissues (in the face, lips, throat, hands, feet, or genitalia) that is nonpitting, nonpruritic, and not accompanied by urticaria. Triggers include emotional stress, physical trauma, infections, physical exertion, and surgery and other medical procedures.
  • Abdominal pain: In a series of 149 patients with hereditary angioedema who had 521 attacks, 49% of the episodes were characterized by isolated abdominal pain.5  Abdominal attacks are generally not associated with fever, peritoneal signs, or leukocytosis.
  • Laryngeal edema occurs in approximately 0.9% of all attacks7 and may be life-threatening, leading to asphyxiation and death.
  • Differential Diagnosis: Some of the rare diagnosis that were discussed: acute intermittent porphyria, familial Mediterranean fever (FMF), mastocytosis, and eosinophilic gastroenteritis.
  • Pathophysiology: Deficiency of C1 inhibitor protein: The majority of cases of hereditary angioedema are caused by either decreased levels (type I) or reduced functionality (type II) of C1 inhibitor. A third subtype (type III) that is associated with different mutations but the same clinical features is characterized by normal quantitative and functional C1 inhibitor levels.2
  • The best screening test: measurement of the level of C4 (which is exhausted as a result of uncontrolled activation of the complement pathway when C1 inhibitor is deficient or dysfunctional); results may be normal in 10% of patients between attacks. Quantification of C1 inhibitor levels can then be performed to differentiate between the low levels in hereditary angioedema type I and the normal levels in hereditary angioedema type II. 
  • Treatment: Food and Drug Administration–approved agents include human plasma–derived C1 inhibitor concentrate, recombinant human C1 inhibitor, icatibant (bradykinin B2 receptor antagonist), and ecallantide (kallikrein inhibitor).9 Each has been shown in randomized, controlled trials to decrease the median time to symptom relief.10-14 The first three therapies may be administered by the patient, whereas ecallantide requires support from a health care professional for management of possible anaphylaxis, which is reported in up to 4% of patients.9 Most treatments are used on-demand, though some patients benefit from long-term prophylaxis.
  • Preprocedure prophylaxis: Preprocedural prophylaxis is recommended for patients undergoing procedures that may trigger an attack (e.g., dental surgery, endotracheal intubation, or an endoscopic procedure). C1 inhibitor concentrate can be administered intravenously before the procedure, or treatment with an anabolic androgen (e.g., danazol or stanozolol) can be started 5 days before and continued for 2 to 5 days after the procedure9; …Fresh frozen plasma may be used as a second-line therapy when these therapies are not available

My take: This case “highlights the importance of maintaining a high clinical suspicion for hereditary angioedema in patients with episodic severe abdominal pain and negative workup for other illnesses” even in patients without other manifestations.

Related blog posts:

Figure 1A (from NEJM twitter feed)

Overlooking Important Detail$ in Hereditary Angioedema Treatment

Posted on by

Several approved treatments are now available for Hereditary Angioedema (HAE) attacks. A recent article highlights the effectiveness in 46 children who received 2237 infusions of nanofiltered C1-esterase inhibitor (C1 INH-nf) treatment (J Pediatr 2013; 162: 1017-22).

Background:  HAE prevalence: 1 in 50,000.  Though it is inherited in an autosomal dominant manner, up to 25% of case are de novo. HAE is characterized by recurrent episodic attacks of subcutaneous edema of the skin, GI tract or upper airway.  Symptoms often present between 4 and 11 years of age.  GI tract symptoms are often recurrent colicky abdominal pain. Triggers for attacks may include infections, emotional stress, and trauma (e.g. bodily contact from play).

This manuscript provides data from 4 prospective clinical trials of  C1 INH-nf (Cinryze).  Most children in this study responded within 30 minutes compared with 2 hours for placebo.  Therapy also reduced the rate of attacks.  One interesting aspect of the study was its lack of any mention of cost.

From UptoDate:  “Cost of first-line therapies — All first-line therapies for acute attacks of HAE are costly. In the US, the cost of one treatment with C1INHRP,ecallantide, or icatibant ranged from $5000 to $10,000.”  Hereditary angioedema: Treatment of acute attacks – UpToDate

From a Hereditary Angioedema – RegenceRx website: “As a preventative therapy, C1 esterase inhibitor (Cinryze) is significantly more costly than other formulary alternatives (~$500,000 per year; ~250 times more than danazol). For acute treatment of an HAE attack, C1 esterase inhibitor (Berinert) and ecallantide (Kalbitor) costs approximately $6,000 to $10,000 per attack. Cost may double if re- treatment is needed within 24 hours.”

Additional reference:

  • -Eur J Pediatr 2012; 171: 1339-48.  Consensus of therapeutic strategies for HAE.