Schlüsselwörter
COVID-19 - Porphyrie - seltene Erkrankungen
Keywords
COVID-19 - porphyria - rare diseases
Introduction
The COVID-19 pandemic has kept the medical world on edge for more than a year. While
the pandemic undoubtedly has direct implications for infected patients and families,
as well as broad social and economic consequences, there is also a need to examine
the pandemic’s effect on patients with non-COVID-19-related diseases. Warnings have
been issued that collateral damages from the pandemic may occur due to delayed diagnoses.
Evidence is accumulating that common life-threatening diseases, such as cardiovascular
diseases and cancer, may experience a delay in diagnosis and treatment during the
pandemic [1]
[2]. People suffering from rare diseases, defined as diseases affecting fewer than 5
per 10000 people, are already a vulnerable patient group during “normal” times. Although
individually rare, collectively, 6–8% of the European population suffer from rare
diseases [3]. These patients often undergo several diagnostic tests, have multiple visits to
different specialists, and receive a conclusive diagnosis only after a long period
[4].
Data from Hong Kong suggest that the COVID-19 pandemic impacts early diagnosis and
appropriate management of rare diseases and resource utilization; it also affects
the physical and mental well-being of people suffering from rare diseases [5].
In early 2021, an additional variable came into the equation: COVID-19 vaccines and
their serious adverse events, including possible fatal thromboembolic side effects
[6]. Of the currently approved vaccines against COVID-19, the administration of the
ChAdOx1 nCoV-19 vaccine has been associated with vaccine-induced immune thrombotic
thrombocytopenia (VITT) and concomitant thromboembolic events, also in unusual anatomical
locations including cerebral venous sinus, splanchnic veins, or portal veins [7]
[8]
[9].
Case report
A 34-year-old physiotherapist presented to the emergency department 4 days after receiving
the first dose of ChAdOx1 nCoV-19 vaccination with a fever that resolved after 3 doses
of 500 mg of paracetamol within 12 hours, pinprick sensations in her chest and thoracic
spine, and dizziness. The patient’s medical history included Hashimoto thyroiditis
under thyroid hormone therapy and an appendectomy 11 years ago; histology showed ulcero-phlegmonous
appendicitis. Vital signs (blood pressure 115/70 mmHg, heart rate 80 beats per minute,
temperature 35.6°C, peripheral oxygen saturation 100% at ambient air) were uneventful;
clinical examination, electrocardiography, and chest x-ray showed no pathological
findings. Laboratory analysis revealed a slightly elevated serum creatinine of 1.01
mg/dL (normal range 0.5–0.9), mild thrombocytopenia of 142 G/L (normal range 150–370),
and a slightly decreased serum sodium of 134 mmol/L (normal range 135–145). D-dimer
and cardiac enzymes were unremarkable. The patient received 1 g metamizole intravenously
and was discharged to home with resolved symptoms after an observation period of 5
hours. Sixteen hours later, she presented again with additional lower abdominal pain,
vomiting, and loose stools. Laboratory findings and a clinical examination were again
unremarkable. Focused abdominal sonography and a plain abdominal film showed no abnormalities.
After an overnight observation period and supportive treatment with metamizole, butylscopolamine
bromide, and crystalloid fluid intravenously, she was discharged home but presented
again to our emergency department on the same day. She reported that her urine had
turned red, and her dizziness had worsened. Laboratory evaluation revealed progressive
thrombocytopenia (128 G/L) and hyponatremia (128 mmol/l), while fibrinogen and D-dimer
were unremarkable. Urine dipstick was highly positive for bilirubin, hemoglobin, and
ketoacids with only slight microhematuria. The patient additionally reported that
she had followed a “low-carb” diet for a few days in an attempt to lose weight (body
mass index 25.6 kg/m2). A pregnancy test was negative, and a gynecological examination was inconspicuous.
An abdominal CT was performed to exclude potential VITT and thrombosis of the splanchnic
veins, revealing no thrombosis or other pathologies. She was admitted for further
observation and supportive therapy. On the next day, the patient reported pollakisuria
and dysuria in addition to lower abdominal pain; a urine dipstick was positive for
nitrite. Urinary tract infection was suspected, and antibiotic therapy with single-shot
fosfomycin (3 g) was administered. The patient claimed progressive weakness, needing
help with walking, and reported progressive lower abdominal pain. As metamizole did
not adequately improve the pain, piritramide was prescribed. The patient could not
eat full meals due to pain and therefore received oral nutritional supplements in
the hospital. The patient’s description of pain was remarkable: a sensation of a burning
ball that exploded in her pelvis.
Progressive hyponatremia and hypertension were noticed over the weekend, and the patient
was subsequently admitted to ICU. Syndrome of inappropriate antidiuretic hormone secretion
(SIADH) was diagnosed based on euvolemic state with reduced serum osmolality (243
mosm/kg [normal range 280–300]), a high urinary osmolarity (479 mosm/kg [normal range
50–120]) and urinary sodium (177 mmol/L), and adequate thyroid function. Therefore,
the patient received fluid restriction and furosemide as symptomatic treatment of
SIADH. Hypertension required treatment with continuous infusion of urapidil for several
hours ([Table 1]).
The reddening of urine already noticed in the emergency department had triggered a
porphyria diagnosis; however, the results were delayed due to the weekend and arrived
when the patient was already in the ICU receiving treatment for SIADH. Porphyrins
(13734.0 g/24 h [normal range 0.0–150.0]), 5-aminolevulinic acid (104.25/mg/24h [normal
range 0.25–6.40]) and porphobilinogen (58.80 mg/24h [normal range 0.10–1.70]) were
highly elevated in the urine. Therefore, the diagnosis of acute hepatic porphyria
was made. Treatment with hemin 3 mg/kg body weight for 5 consecutive days was initiated,
and all potentially prophyrogenic drugs were stopped and replaced by safe alternatives.
We chose to give hemin for 1 additional day because of the severity of symptoms at
the start of treatment. Initiation of hemin was followed by the rapid improvement
of the patient’s blood pressure and hyponatremia ([Fig. 1]A). Also, her abdominal pain improved rapidly over the next few days, leading to
a rapid reduction in the need for pain medication. She was discharged from ICU with
nearly normalized serum sodium and without abdominal pain, but she reported residual
dysesthesia in her legs which gradually improved over the following weeks. At ICU
discharge, urinary porphyrins (402.7 g/24h), 5-aminolevulinic acid (2.21 mg/24h),
and porphobilinogen (5.12 mg/24h) were markedly improved. Despite these low levels
of porphyrins in urine, urine changed to a red-orange color after 30 minutes of exposure
to daylight ([Fig. 1]B).
Fig. 1
A Blood pressure and serum sodium during the hospitalization in relation to medication.
After transfer to ICU Urapidil, continuous infusion was necessary for blood pressure
control. Dexmedetomidin was administered overnight for sedation. Before the diagnosis
of porphyria was made on day 7 of the hospital stay, the patient also received potentially
unsafe drugs for porphyria. B Urine of the patient at asymptomatic state (fresh and after 30 minutes of daylight
exposure). Darkening of urine in acute hepatic porphyrias is due to the accumulation
of porphyrins and/or porphobilin in the urine.
Further analysis of porphyrins in feces and genetic analysis confirmed the diagnosis
of acute intermittent porphyria. The most likely trigger of the disease was the “low-carb”
ketogenic diet the patient initiated a few days before symptom onset. The patient
received counseling on avoiding prophyrogenic drugs based on the NAPOS list (http://www.drugs-porphyria.org ) and carbohydrate restriction to prevent further acute attacks. No further attacks
occurred in the observation period of the subsequent 5 months.
Table 1 Laboratory findings during hospitalization.
|
Parameter
|
Unit
|
Normal range
|
Hospital admission
|
ICU admission
|
ICU discharge
|
Follow up
|
|
White blood count
|
G/L
|
4.4–11.3
|
3.99
|
9.59
|
6.16
|
5.38
|
|
Hemoglobin
|
G/L
|
12.0–15.3
|
12.6
|
13.1
|
12.3
|
11.3
|
|
Platelets
|
G/L
|
150–370
|
128
|
223
|
219
|
216
|
|
Creatinine
|
mg/dL
|
0.5–0.9
|
1.01
|
0.93
|
0.74
|
0.84
|
|
Serum osmolality
|
mosm/kg
|
280–300
|
–
|
243
|
–
|
|
|
Serum sodium
|
mmol/L
|
135–145
|
128
|
116
|
131
|
138
|
|
|
|
|
|
|
|
|
|
Porphyrins
|
g/24h
|
0–150
|
13,734.0
|
–
|
402.7
|
–
|
|
5-aminolevulinic acid
|
mg/24h
|
0.25–6.40
|
104.25
|
–
|
2.21
|
–
|
|
Porphobilinogen
|
mg/24h
|
0.10–1.70
|
58.80
|
–
|
5.12
|
–
|
Discussion
During clinical decision-making, the focus may be diverted to COVID-19 disease and
associated medical problems, such as vaccine-related side effects, while “classic”
rare diseases may be overlooked. We report the case of a 34-year patient with her
first attack of acute hepatic porphyria most likely triggered by the initiation of
a “low-carb” ketogenic diet in the attempt to lose weight. Additionally, the patient
received vaccination against COVID-19 a few days before symptom onset. In our case,
the patient was fully explored regarding VITT, including several blood tests and a
CT scan of the abdomen.
Side effects of ChAdOx1 nCoV-19 vaccination include fatigue, myalgia, or fever, while
serious side effects like allergic reactions and VITT may also occur [10]. Increasing venous thromboembolism and VITT rates have been described in 18–65-year-old
recipients of ChAdOx1 nCoV-19 vaccination. The underlying pathway contributing to
VITT may be comparable to autoimmune heparin-induced thrombocytopenia contributed
by platelet factor 4-polyanion complexes [7]
[8]
[9]. In our case, vaccine-induced thrombosis of the splanchnic veins, which was suspected
due to initial progressive thrombocytopenia and symptom progression, was quickly ruled
out by negative d-dimers, absent evidence of splanchnic thrombosis on CT scan, and
finally by spontaneous recovery of thrombocytopenia. However, the patient’s symptoms
could not be explained after the initial diagnostic checkup and even worsened, leading
to further exploration.
Acute pain is the cardinal symptom of acute hepatic porphyria, but management and
pain assessment have been poorly studied in these patients. Pain during an attack
is usually severe enough to require opioid analgesics. Mild pain can be treated with
acetaminophen [11], while metamizole is a potentially porphyrogenic drug [12]. In our case, the patient described the pain in a unique way and required treatment
with opioid analgesics. The description that her urine had a reddish color was the
trigger to initiate the diagnosis of acute hepatic porphyria; however, the likelihood
of this diagnosis was first considered low. In our patient, a urine dipstick positive
for nitrite together with pollakisuria, dysuria, and lower abdominal pain, led to
the much more likely suspicion of a urinary tract infection in a young woman [13]. However, autonomous bladder dysfunction with dysuria may also be symptoms of acute
hepatic porphyria [14]. Tachycardia and hypertension in acute hepatic porphyria may be signs of the affection
of the autonomous nervous system or may be secondary to acute pain; in our patient,
blood pressure increases corresponded with pain attacks, but hypertension also required
continuous intravenous therapy over several hours in addition to opioid analgesics.
As in our patient, nausea and vomiting also often accompany abdominal pain in acute
hepatic porphyria and may be caused by visceral neuropathy [14].
The most dangerous symptom in our patient was progressive hyponatremia. In patients
with hyponatremia, hydration status, serum, and urine osmolality, as well as urine
sodium, should be investigated to allow for differential diagnoses. Mild to severe
hyponatremia occurs in 25–60% of cases during an acute porphyria attack, and hyponatremia
is also a marker of the severity of the attack [15]. SIADH is the pathophysiological basis for hyponatremia in acute hepatic porphyria.
The etiology of SIADH during attacks of acute hepatic porphyria is multifactorial:
abdominal pain is a stimulus for the synthesis of ADH. The excess of ADH acts on the
V1a receptors of the vasculature, increasing peripheral resistance and raising central
blood pressure, and on the renal V2 receptors, preventing the kidney from adequately
eliminating any water overload. Acute attacks are also frequently accompanied by paralytic
ileus that causes intestinal sequestration of water and electrolytes, which, in turn,
stimulates the secretion of angiotensin II. The third ventricle is equipped with receptors
for angiotensin II, which directly stimulate ADH secretion [15].
Treatment of SIADH in acute hepatic porphyria is based on 2 pillars: general treatment
of SIADH and specific therapy of acute hepatic porphyria. General treatment of SIADH
includes fluid restriction and loop diuretics [16]
[17]. Tolvaptan is also considered to be useful in SIADH caused by acute hepatic porphyria
[15]. Specific treatment of an acute hepatic porphyria attack is facilitated with intravenous
hemin (3mg/kg body weight per day, dissolved in albumin, for 4 consecutive days) [18] that is taken up into hepatocytes and represses synthesis of the first enzyme in
the heme biosynthetic pathway, delta-aminolevulinic acid synthase. This decreases
the accumulation of heme precursors and their byproducts, as documented by rapid and
dramatic reductions in plasma and urinary porphobilinogen and delta-aminolevulinic
acid. Although large randomized controlled trials are lacking, evidence is strong
that hemin is effective and safe as an immediate therapeutic agent in acute hepatic
porphyria [19]. When hemin is unavailable, carbohydrate loading through intravenous glucose administration
can be used as a temporary measure until hemin is available. Glucose and other carbohydrates
reduce the excretion of porphyrin precursors by downregulating hepatic delta-aminolevulinic
acid synthase, an effect mediated by decreases in the peroxisome proliferator-activated
receptor-gamma coactivator 1-alpha. However, the effect of glucose is weak compared
to the effect of hemin [20]. In addition, intravenous glucose can cause and aggravate hyponatremia and therefore
would not have been feasible in our patient [15]. Very recently, the RNA interference (RNAi) therapy Givosiran, which reduces the
annualized attack rate by 74%, became available for patients with recurrent attacks
[21]
[22].
Early diagnosis of acute hepatic porphyria is important for the outcome of the disease.
Attacks are less severe and have a lower risk for ICU admission in patients already
diagnosed with porphyria as treatment is usually initiated earlier, and triggers are
consistently avoided [23]. However, the delay between symptom onset and diagnosis may be delayed for several
years—a mean delay of 15 years was reported in a cohort from the USA. [24] Under exceptional circumstances, such as during the current COVID-19 pandemic but
also during other situations such as a heatwave, a political conflict, or even during
a football game, [25] the perception of medical professionals may (but of course should not) be shifted,
leading to misdiagnosis. Novel approaches, such as machine learning and knowledge
engineering, can be helpful to mitigate illusory correlations and metacognition errors
in medicine, especially in the emergency medicine setting [26], and detect rare diseases in electronic patient records [27].
Conclusion
We managed to diagnose acute hepatic porphyria in a young woman at her first attack.
It is important to be vigilant and not to forget other common but also uncommon disorders,
such as acute hepatic porphyria, as a rare trigger of SIADH [28] and potentially life-threatening disease during the current challenges of the pandemic.
The European Porphyria Network (EPNET, www.porphyria.net) issued a statement that “as with all other vaccines, the COVID-19 vaccines carry
no additional risk in acute porphyria, and we recommend that people with acute intermittent
porphyria, porphyria variegata or hereditary coproporphyria accept vaccination when
this is offered” [29]. Although the COVID-19 vaccination, especially in combination with a ketogenic diet,
cannot be completely excluded as a trigger for the acute porphyria attack, we believe
that it was a “red herring” in our case.
Ethical Approval and Consent to participate
Not applicable (Case report)
Consent for publication
The patient gave written consent to this publication.
Availability of supporting data
The dataset used and/or analyzed during the current study is available from the corresponding
author on reasonable request.
Authors’ contributions
PJ, GH, ACR, PE, and VS were involved in patient management. All authors provided
critical intellectual content to the manuscript. AH and VS created the visualization.
All authors approved the final manuscript.
